(4,4-difluorobut-3-enylthio)-substituted heterocyclic or carbocyclic ring compounds having pesticidal activity

ABSTRACT

A compound having the formula R--S(O) n  CH 2  CH 2  CH═CF 2 , or a salt thereof, wherein R is a phenyl group or a heterocyclic group selected from furyl, thienyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,4-triazinyl and 1,3,5-triazinyl groups, said phenyl or heterocyclic group being optionally substituted by optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, cycloalkyl, alkylcycloalkyl, alkoxy, alkenyloxy, alkynyloxy, hydroxyalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted heteroaryloxyalkyl, haloalkyl, haloalkenyl, haloalkynyl, haloalkoxy, haloalkenyloxy, haloalkynyloxy, halogen, hydroxy, cyano, nitro, --NR7R8, --NR7COR8, --NR7CSR8, --NR7SO2R8, --N(SO2R7)(SO2R8), --COR7, --CONR7R8, -alkylCONR7R8, --CR7NR8, --COOR7, --OCOR7, --SR7, --SOR7, --SO2R7, -alkylSR7, -alkylSOR7, -alkylSO2R7, --OSO2R7, --SO2NR7R8, --CSNR7R8, --SiR7R8R9, --OCH2CO2R7, --OCH2CH2CO2R7, --CONR7SO2R8, -alkylCONR7SO2R8, --NHCONR7R8, --NHCSNR7R8, or an adjacent pair of R1, R2, R3, R4, R5 and R6 when taken together form a fused 5- or 6-membered carbocyclic or heterocyclic ring; and R7, R8 and R9 are each independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, optionally substituted aryl or optionally substituted arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, halogen, or hydroxy.

The present invention relates to novel heterocyclic and phenylderivatives having nematicidal, insecticidal and acaricidal activity, toprocesses for their preparation, to compositions containing them, and tomethods for killing or controlling nematode, insect or acarid pestsusing them.

According to the present invention there is provided a compound offormula (I), or a salt thereof, wherein n is 0, 1 or 2; and R is a groupof formula (II) to (XXI), wherein:

the S(O)nCH2CH2CH═CF2 group is at least one of R1 (when attached to acarbon atom), R2, R3, R4, R5 or R6;

R1 (when attached to a carbon atom), R2, R3, R4, R5 and R6 are eachindependently hydrogen optionally substituted alkyl, optionallysubstituted alkenyl, alkynyl, cycloalkyl, alkylcycloalkyl, alkoxy,alkenyloxy, alkynyloxy, hydroxyalkyl, alkoxyalkyl, optionallysubstituted aryl, optionally substituted arylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,optionally substituted aryloxy, optionally substituted arylalkoxy,optionally substituted aryloxyalkyl, optionally substitutedheteroaryloxy, optionally substituted heteroarylalkoxy, optionallysubstituted heteroaryloxyalkyl, haloalkyl, haloalkenyl, haloalkynyl,haloalkoxy, haloalkenyloxy, haloalkynyloxy, halogen, hydroxy, cyano,nitro, --NR7R8, --NR7COR8, --NR7CSR8, --NR7SO2R8, --N(SO2R7)(SO2R8),--COR7, --CONR7R8, -alkylCONR7R8, --CR7NR8, --COOR7, --OCOR7, --SR7,--SOR7, --SO2R7, -alkylSR7, -alkylSOR7, -alkylSO2R7, --OSO2R7,--SO2NR7R8, --CSNR7R8, --SiR7R8R9, --OCH2CO2R7, --OCH2CH2CO2R7,--CONR7SO2R8, -alkylCONR7SO2R8, --NHCONR7R8, --NHCSNR7R8, or an adjacentpair of R1, R2, R3, R4, R5 and R6 when taken together form a fused 5- or6-membered carbocyclic or heterocyclic ring,

R1 (when attached to a nitrogen atom) is hydrogen, optionallysubstituted alkyl, cycloalkyl, alkylcycloalkyl, hydroxyalkyl,alkoxyalkyl, optionally substituted aryl, optionally substitutedarylalkyl, optionally substituted aryloxyalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroaryloxyalkyl, haloalkyl, hydroxy, cyano, nitro,--NR7R8, --NR7COR8, NR7CSR8, --NR7COOR8, --NR7SO2R8, --N(SO2R7)(SO2R8),--COR7, --CONR7R8, -alkylCONR7R8, --CR7NR8, --COOR7, --OCOR7, --SOR7,--SO2R7, -alkylSR7, -alkylSOR7, -alkylSO2R7, --OSO2R7, --SO2NR7NR8,--SR7, --SOR7, --SO2R7, --CSNR7R8, --SiR7R8R7, --OCH2CO2R7,--OCH2CH2CO2R7, --CONR7SO2R8, -alkylCONR7SO2R8, --NHCOR7R8, or--NHCSR7R8, and

R7, R8 and R9 are each independently hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, alkynyl, optionally substitutedaryl, optionally substituted arylalkyl, haloalkyl, haloalkenyl,haloalkynyl, halogen, or hydroxy.

We would explain that, for ease of reference only, the substituents onthe R group have been named in accordance with their position on this Rgroup. For example, when R has the formula (II), substituents R2, R3, R4and R5 are in positions 2, 3, 4, and 5, respectively, on the ring. Forthe avoidance of doubt, the --S(O)nCH2CH2CH═CF2 group can be at any ofthe substituent positions indicated by R1 (when attached to a carbonatom) to R6.

When any one of R1 to R9 is an alkyl group, or contains aralkyl moiety,it may be straight or branched chain and is preferably C1-6 alkyl, evenmore preferably C14 alkyl, for example methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl or t-butyl. When the alkylgroup is acting as a "linking" group, ie R-alkyl-, for example inR-alkylsr77, C1-4 alkyl or C1-2 alkyl are particularly preferred.

When any one of R1 to R8 is a substituted alkyl group, or contains asubstituted alkyl moiety, it may comprise one or more subsistenceschosen from halogen, nitro, cyano, --COOR7 or a salt thereof, hydroxy,alkoxy, alkoxyimino, alkoxycarbonyl, carbamoyl, mono- ordi-alkylcarbamoyl, amino, mono- or di-alkylamino, acylamido (preferablyC1-6 acylamido), alkanesulfonyl, and arylsulfonyl, which may itself besubstituted with halogen, alkoxy or nitro.

When any one of R1 to R8 is an alkenyl or alkynyl group, or contains analkenyl or alkynyl moiety, it may be straight or branched chain and ispreferably C2-6 alkenyl or C2-6 alkynyl, even more preferably C2-4alkenyl or C2-4 alkynyl, for example vinyl, allyl, but-3-enyl,3-methyl-but-3-enyl, ethynyl or propargyl.

When any one of R1 to R8 is a substituted alkenyl group, or contains asubstituted alkenyl moiety, it may comprise one or more subsitutentschosen from halogen, COOR7 or a salt thereof, hydroxy, nitro and cyano.

When any one of R1 to R6 is a cycloalkyl or alkylcycloalkyl group, orcontains a cycloalkyl or allylcycloalkyl moiety, it is preferably C3-6cycloalkyl or C4-7 alkylcycloalkyl, for example, cyclopropyl,cyclopentyl, cyclohexyl or methylcyclopropyl.

When any one of R1 to R6 is an alkoxy, alkenyloxy, alkynyloxy oralkoxyalkyl group, or contains such a moiety, it is preferably C1-6alkoxy, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,iso-butoxy, sec-butoxy and t-butoxy; C2-6 alkenyloxy, for example,vinyloxy, allyloxy, but-3-enyloxy and 3-methylbut-3-enyloxy; C2-6alkynyloxy, for example, propargyloxy; C2-6 monoalkoxyalkyl, forexample, methoxymethyl, methoxyethyl and ethoxymethyl; or C3-6dialkoxyalkyl, for example, dimethoxymethyl and diethoxymethyl.

When any one of R1 to R9 is aryl, or contains an aryl moiety, it ispreferably C6-10 aryl, more preferably it is phenyl. When any one of R1to R9 is arylalkyl, it is preferably C6-10 aryl-methyl or C6-10aryl-ethyl, even more preferably benzyl or phenethyl.

When any one of R1 to R6 is heteroaryl, or contains a heteroaryl moiety,it is preferably a 5 or 6 membered ring containing at least one O, N orS atom as the heteroatom, for example, pyridine, pyrrole, pyrazine,furan or thiophene. When any one of R1 to R6 is heteroarylalkyl, it ispreferably heteroaryl-C1-2 alkyl.

When any one of R1 to R9 is a substituted aryl, arylalkyl, heteroaryl,or heteroarylalkyl group, it may comprise one or more substituentschosen from allyl, alkoxy, haloalkyl, halogen, hydroxy, COOR7 (or a saltthereof), aminosulfonyl, cyano or nitro. Examples of these groups are4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-nitrophenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-aminosulfonylphenyl,4-chlorobenzyl, 4-fluorobenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 4-nitrobenzyl and 4-methylbenzyl.

When any one of R1 to R6 is a aryloxy or arylalkoxy group, it ispreferably phenoxy, benzyloxy or phenethoxy.

When any one of R1 to R6 is a substituted aryloxy, arylalkoxy,heteroaryloxy or heteroarylalkoxy group, it may comprise one or moresubstituents chosen from alkyl, alkoxy, haloalkyl, hydroxy, cyano ornitro. Examples of these groups are 4-methylphenoxy, 4-chlorophenoxy,4-fluorophenoxy, 4-nitrophenoxy, 3-trifluoromethylphenoxy,4-trifuoromethylphenoxy 4-chlorobenzyloxy, 4-fluorobenzyloxy,3-trifluoromethylbenzyloxy, 4-triuoromethylbenzyloxy, 4-nitrobenzyloxyand 4-methylbenzyloxy.

When any one of R1 to R9 is halogen, or contains a halogen moiety, it ispreferably fluorine, chlorine, bromine or iodine. Even more preferably,it is fluorine, chlorine or bromine.

When any one of R1 to R9 is a haloalkyl, haloalkenyl or haloalkynylgroup, it may contain one or more halogen atoms, preferably chlorine,fluorine or bromine. Examples of these groups are fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl,2,2-difluoroethenyl, 3,3-dichloroprop-2-enyl, 2-chloroprop-2-enyl,3,4,4-trifluorobut-3-enyl, 4-fluorobut-3-enyl, 4,4-difluorobut-3-enyland 3-methyl-4,4-difluorobut-3-enyl.

When any one of R1 to R6 is a haloalkoxy group, a haloalkenyloxy groupor a haloalkynyloxy group, it may contain one or more halogen atoms,preferably chlorine, fluorine or bromine. Examples of the preferred C1-6alkoxy, C2-6 alkenyloxy and C2-6 alkynyloxy groups are tichloromethoxy,fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy,2,2,2-tifluoroethoxy, pentafluoroethoxy, 1,1,2,2-tetrafluoroethoxy,2,2-difluoroethenyloxy, 3,4,4-trifluorobut-3-enyloxy,4-fluorobut-3-enyloxy, 4,4-difluorobut-3-enyloxy,3-methyl-4,4-difluorobut-3-enyloxy, 2-chloroprop-2-enyloxy and3,3-dichloroprop-2-enyloxy.

When any one of R1 to R6 is the group --NR7R8, it is preferably --NH2; amono-alkylamino group, for example, methylamino and ethylamino; or adi-alkylanino group, for example, dimethylamino and diethylamino.

When any one of R1 to R6 is the group --NR7COR8, it is preferably--NHCHO; a C2-6 acylamino group, for example --NHCOCH3, --NHCOC2H5; orbenzamido, which may be substituted with one or more substituents chosenfrom halogen, for example, chlorine, fluorine and bromine; alkyl, forexample, methyl and ethyl; alkoxy, for example, methoxy and ethoxy;haloalkyl, for example, chloromethyl, fluoromethyl, trifluoromethyl and2,2,2-trifluoroethyl; haloalkoxy, for exarmple, trifluoromethoxy and2,2,2-tifluoroethoxy; hydroxy; cyano and nitro.

When any one of R1 to R6 is --NR7CSR8, R7 and R8 are preferably alkyl,for example methyl and ethyl.

When any one of R1 to R6 is the group --NR7SO2R8, it is preferably anallanesulfonamido group, for example, --NHSO2CH3 and --NHSO2C2H5.

When any one of R1 to R6 is the group --N(SO2R7)(SO2R8), it ispreferably a di-(alkanesulfonyl)amino group, for example, --N(SO2CH3)2and --N(SO2C2H5)2.

When any one of R1 to R6 is the group --COR7, it is preferably a C1-6acyl group; or an optionally substituted benzoyl group. The benzoyl maybe substituted with one or more substituents chosen from halogen, forexample, chlorine, fluorine and bromine; alkyl, for example, methyl andethyl; alkoxy, for example, methoxy and ethoxy; haloalkyl, for example,chloromethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl;haloalkoxy, for example, trifluoromethoxy and 2,2,2-tifluoroethoxy;hydroxy; cyano and nitro. Examples of preferred --COR7 groups areacetyl, propionyl, n-butanoyl, 4-chlorobenzoyl, fluorobenzoyl,4-bromobenzoyl, 4-methylbenzoyl and 4-trifluoromethylbenzoyl.

When any one of R1 to R6 is the group --CONR7R8, it is preferably--CONH2; an N-alkyl-carboxamido group, for example --CONHCH3, --CONHC2H5and --CONHCH2CH2CH3; or an N,Ndialkyl-caboxamido group, for example--CON(CH3)2, --CON(CH3(C2H5) and --CON(C2H5)2.

When any one of R1 to R6 is the group -alkylCONR7R8, it is preferably--C1-4 alkylCONR7R8.

When any one of more of R1 to R6 is the group --CR7NR8, it is preferably--CH═NOH.

When any one of R1 to R6 is the group --COOR7, it is preferably --COOH;an alkoxycarbonyl group, for example methoxycarbonyl and ethoxycarbonyl;or a haloalkenyloxycarbonyl group, for example3,4,4-tifluorobut-3-enyloxycarbonyl, 4-fluorobut-3-enyloxycarbonyl,4,4-difluorobut-3-enyloxycarbonyl and3-methyl-4,4-difluorobut-3-enyloxycarbonyl.

When any one of R1 to R6 is the group --OCOR7, it is preferably a C2-6acyloxy group, for example --OCOCH3 and --OCOC2H5, or an optionallysubstituted benzoyloxy group. The benzoyloxy group may COMPRISE one ormore substituents chosen from halogen, for example, chlorine, fluorineand bromine; alkyl, for example, methyl and ethyl; alkoxy, for example,methoxy and ethoxy; haloalkyl, for example, chloromethyl, fluoromethyl,trifluoromethyl and 2,2,2-tifuoroethyl; haloalkoxy, for example,trifluoromethoxy and 2,2,2-trifluoroethoxy; hydroxy; cyano; and nitro.

When any one of R1 to R6 is the group --SR7, R7 is preferably hydrogen,optionally substituted alkyl, optionally substituted alkenyl, alkynyl,haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, oroptionally substituted arylalkyl. Examples of the preferred C1-6alkylthio (C1-4 alkyl being especially preferred), C2-6 alkenylthio orC2-6 alkynylthio groups are methylthio, ethylthio, n-propylthio,iso-propylthio, n-butylthio, iso-butylthio, secbutylthio, t-butylthio,allylthio, but-3-enylthio, 3-methylbut-3-enylthio and propargylthio.Examples of the preferred C1-6 haloalkylthio (C1-4 alkyl beingespecially preferred), C2-6 haloalkenylthio or C2-6 haloalkynylthiogroups are fluoromethylthio, difluoromethylthio, trifluoromethylthio,trichloromethylthio, 2-fluoroethylthio, 2,2,2-trifluoroethylthio,3-fluoro-n-propylthio, pentafluoroethylthio, 2-chloroprop-2-enylthio,3,3-dichloroprop-2-enylthio, 3,4,4-triluorobut-3-enylthio,4-fluorobut-3-enylthio, 4,4-difluorobut-3-enylthio and3-methyl-4,4-difluorobut-3-enylthio. An example of the preferred C6-10arylthio and C6-10 aryl-C1-2alkylthio groups is3-tifluoromethylbenzylthio.

When any one of R1 to R6 is the group --SOR7, it is preferably analkanesulfinyl, alkenylsulfinyl or alkynylsulfinyl group, for examplemethanesulfinyl or ethanesulfinyl; or a haloalkanesulfinyl,haloalkenylsulfinyl or haloalkynylsulfinyl group, for exampletrifiuoromethanesulfinyl. In another preferred embodiment --SOR7 ispreferably --SOF, --SOBr or --SOCl.

When any one of R1 to R6 is the group --SO2R7, it is preferably analkanesulfonyl, alkenylsulfonyl, alkynylsulfonyl, a haloalkanesulfonyl,haloalkenylsulfonyl, haloalkynylsulfonyl group; or an optionallysubstituted benzenesulfonyl group. The benzenesulfonyl group maycomprise one or more substituents chosen from halogen, for example,chlorine, fluorine and bromine; alkyl, for example, methyl and ethyl;alkoxy, for example, methoxy and ethoxy; haloalkyl, for example,chloromethyl, fluoromethyl, trifluoromethyl and 2,2,2-tifluoroethyl;haloalkoxy such as trifluoromethoxy and 2,2,2-trifluoroethoxy; hydroxy;cyano and nitro. Examples of such groups are methanesulfonyl,ethanesulfonyl, trifiuoromehanesulfonyl, and 4-methylbenzenesulfonyl. Inanother preferred embodiment --SO2R7 is preferably --SO2F, --SO2Br or--SO2Cl.

It will thus be appreciated that the R group of formula (II) to (X) cancomprise more than one --S(O)nCH2CH2CH═CF2 group. Preferably the R groupcontains one or two such substituents.

When any one of R1 to R6 is the group --OSO2R7, it is preferably analkanesulfonyloxy group or an optionally substituted benzenesulfonyloxygroup. The benzenesulfonyl may be substituted with one or moresubstituents chosen from halogen, for example, chlorine, fluorine andbromine; alkyl, for example, methyl and ethyl; alkoxy, for example,methoxy and ethoxy; haloalkyl, for example, chloromethyl, fluoromethyl,tifluoromethyl and 2,2,2-trifluoroethyl; haloalkoxy, for example,trfluoromethoxy and 2,2,2-tifluoroethoxy; hydroxy; cyano; and nitro.

When any one of R1 to R6 is the group, --SO2NR7R8, it is preferably--SO2NH2; an alkylaminosulfonyl group, for example, --SO2NHCH3 and--SO2NHC2H5; or a dialkylaminosulfonyl group, for example, --SO2N(CH3)2and --SO2N(C2H5)2.

When any one of R1 to R6 is the group --CSNR7R8 it is preferably--CSNH2, --CSNHCH3 or --CSN(CH3)2.

When any one of R1 to R6 is the group --SSiR7R8R9, it is preferably atrialkylsilyl group, for example, trimethylsilyl and triethylsilyl.

When any one of R1 to R6 is the group --OCH2CO2R7, it is preferably analkoxycarbonylmethoxy group, for example, methoxycarbonylmethoxy andethoxycarbonylmethoxy.

When any one of R1 to R6 is the group --OCH2CH2CO2R7, it is preferably aalkoxycarbonylethoxy group, for example, methoxycarbonylethoxy andethoxycarbonylethoxy.

When any one of R1 to R6 is the group --CONR7SO2R8, it is preferably anN-alkanesulfonylcarboxamido group or anN-alkyl-N-alkanesulfonylcarboxamido group, for example,N-(methanesulfonyl)-carboxamido andN-methyl-N4-methanesulfonyl)carboxamido.

When any one or more of R1 to R6 is the group -alkylCONR7SO2R8, R7 andR8 are preferably alkyl groups, for example, ethyl and methyl.

When any one of R1 to R6 is --NHCONR7R8, R7 and R8 are preferably alkylgroups, for example, ethyl and methyl.

When any one of R1 to R6 is --NHCSNR7R8, R7 and R8 are preferably alkylgroups, for example, ethyl and methyl.

When an adjacent pair of R1, R2, R3, R4, R5 and R6 taken together form afused 5- or 6-membered carbocyclic or heterocyclic ring, preferablycontaining two oxygen atoms, the pair of substituents taken together ispreferably --(CH2)3--, --(CH2)4--, --CH═CH--CH═CH--, --O--CH2--O--,optionally substituted with one or two halogen atoms or methyl groups,for example --O--CHF--O-- or --O--CF2--O--, --O--CH(CH3)--O--,--O--C(CH3)2--O-- or --O--(CH2)2--O--.

According to an especially preferred embodiment of the present inventionR1 (when attached to a carbon atom) to R6 are each independentlyhydrogen; nitro; halogen; cyano; --CH═NOH; C1-4 alkyl; C1-4 haloalkyl;C2-4 alkenyl; C2-4 haloalkenyl; cyclopropyl; hydroxy; C1-4 alkoxy; C2-4alkoxyallyl; --COOH; C2-4 alkoxycarbonyl; C3-4 haloalkenyloxycarbonyl;--CONH2; mono or di-C1-2 alkylaminocarbonyl; C2-4 alkanecarbonyl;--CONHSO2 C1-4 alkyl, preferably --CONHSO2CH3; phenyl optionally mono-or di- substituted with groups independently chosen from halogen, nitro,C1-4 alkyl, C1-4 alkoxy or aminosulfonyl; benzyl optionally mono- or di-substituted with groups independently chosen from halogen, nitro, C1-4alkyl or C1-4 alkoxy; phenoxy optionally mono- or di- substituted withgroups independently chosen from halogen, cyano, C1-4 alkyl or C1-4alkoxy; amino optionally mono- or di- substituted with CiA allyl groups;--SH C1-4 alkylthio; benzylthio optionally mono- or di- substituted withgroups independently chosen from halogen or C2-4 haloalkyl; C1-4alkenylthio; C2-4 haloalkenylthio; a second S(O)nCH2CH2CH═CF2 group;C1-4 alkanesulfonyl; C1-4 haloalkanesulfonyl; fluorosulfonyl; mono- ordi- C1-4 alkylsulfamoyl; a 5 or 6 -membered heteroaryl group, forexample, furyl, pyrazinyl, pyridinyl or thienyl, optionally substitutedwith halogen; or any adjacent pair forms a fused 5- or 6 carbocyclic orheterocyclic ring, and

R1(when attached to a nitrogen atom) is hydrogen; nitro; cyano;--CH═NOH; C1-4 alkyl; C1-4 haloalkyl; cyclopropyl; hydroxy; --COOH; C2-4alkoxycarbonyl; C2-4 haloalkenyloxycarbonyl; --CONH2; mono or di-C1-2alkylaminocarbonyl; C2-4 alkanecarbonyl; --CONHSO2 C1-4 alkyl,preferably --CONHSO2CH3; phenyl optionally mono- or di- substituted withgroups independently chosen from halogen, nitro, C1-4 alkyl, C1-4 alkoxyor aminosulfonyl; benzyl optionally mono- or di- substituted with groupsindependently chosen from halogen, nitro, C1-4 alkyl or C1-4 alkoxy;phenoxy optionally mono- or di- substituted with groups independentlychosen from halogen, cyano, C1-4 alkyl or C1-4 alkoxy; amino optionallymono- or di- substituted with C1-4 alkyl groups; --SH; C1-4 alkylthio;benzylthio optionally mono- or di- substituted with groups independentlychosen from halogen or C2-4 haloalkyl; C1-4 alkenylthio; C2-4haloalkenylthio; a second S(O)nCH2CH2CH2CH═CF2 group; C1-4alkanesulfonyl; C1-4 haloalkanesulfonyl; fluorosulfonyl; mono- or di-C1-1-4 alkylsulfamoyl; a 5 or 6 -membered heteroaryl group, for example,furyl, pyrazinyl, pyridinyl or thienyl, optionally substituted withhalogen.

The following Tables give examples of compounds according to theinvention. Examples of compounds of Formula (II) according to theinvention are set ##STR1## out in Table II.

                                      TABLE II    __________________________________________________________________________    No. R2          R3           R4 R5    __________________________________________________________________________    II.1        2-SCH2CH2CH═CF2                    3-H          4-H                                    5-H    II.2        2-SOCH2CH2CH═CF2                    3-H          4-H                                    5-H    II.3        2-SO2CH2CH2CH═CF2                    3-H          4-H                                    5-H    II.4        2-SCH2CH2CH═CF2                    3-H          4-H                                    5-CH3    II.5        2-SOCH2CH2CH═CF2                    3-H          4-H                                    5-CH3    II.6        2-SO2CH2CH2CH═CF2                    3-H          4-H                                    5-CH3    II.7        2-CH3       3-SCH2CH2CH═CF2                                 4-H                                    5-H    II.8        2-CH3       3-SOCH2CH2CH═CF2                                 4-H                                    5-H    II.9        2-CH3       3-SO2CH2CH2CH═CF2                                 4-H                                    5-H    __________________________________________________________________________

Examples of compounds of Formula (II) according to the invention are set##STR2## out in Table III.

                  TABLE III    ______________________________________    No.  R2              R3     R4     R5    ______________________________________    III.1         2-SCH2CH2CH═CF2                         3-H    4-H    5-H    III.2         2-SOCH2CH2CH═CF2                         3-H    4-H    5-H    III.3         2-SO2CH2CH2CH═CF2                         3-H    4-H    5-H    III.4         2-SCH2CH2CH═CF2                         3-H    4-H    5-CHO    III.5         2-SCH2CH2CH═CF2                         3-H    4-H    5-CH2OH    III.6         2-SCH2CH2CH═CF2                         3-H    4-H    (E) 5-CH═NOH    III.7         2-SCH2CH2CH═CF2                         3-H    4-H    (Z) 5-CH═NOH    III.8         2-SCH2CH2CH═CF2                         3-H    4-H    5-CN    III.9         2-SCH2CH2CH═CF2                         3-H    4-H    5-COCH3    III.10         2-SCH2CH2CH═CF2                         3-H    --CH═CH--CH═CH--    III.11         2-SOCH2CH2CH═CF2                         3-H    --CH═CH--CH═CH--    III.12         2-SO2CH2CH2CH═CF2                         3-H    --CH═CH--CH═CH--    ______________________________________

Examples of compounds of Formula (IV) according to the invention are set##STR3## out in Table IV.

                                      TABLE IV    __________________________________________________________________________    No.       R3          R4        R5    __________________________________________________________________________    IV.1       3-C6H5      4-H       5-SCH2CH2CH═CF2    IV.2       3-C6H5      4-H       5-SOCH2CH2CH═CF2    IV.3       3-C6H5      4-H       5-SO2CH2CH2CH═CF2    IV.4       3-CN        4-H       5-SCH2CH2CH═CF2    IV.5       3-Cl        4-H       5-SCH2CH2CH═CF2    IV.6       3-CF3       4-H       5-SCH2CH2CH═CF2    IV.7       3-CH3       4-CONH2   5-SCH2CH2CH═CF2    IV.8       3-CH3       4-COOCH2CH3                             5-SCH2CH2CH═CF2    IV.9       3-CH3       4-COOH    5-SCH2CH2CH═CF2    IV.10       3-CH3       4-H       5-SCH2CH2CH═CF2    IV.11       3-H         4-Cl      5-SCH2CH2CH═CF2    IV.12       3-H         4-CN      5-SCH2CH2CH═CF2    IV.13       3-H         4-CN      5-SOCH2CH2CH═CF2    IV.14       3-H         4-CN      5-SO2CH2CH2CH═CF2    IV.15       3-H         4-CF3     5-SCH2CH2CH═CF2    IV.16       3-H         4-H       5-SCH2CH2CH═CF2    IV.17       3-H         4-NO2     5-SCH2CH2CH═CF2    IV.18       3-H         4-SCH2CH2CH═CF2                             5-CN    IV.19       3-H         4-SCH2CH2CH═CF2                             5-CF3    IV.20       3-SCH2CH2CH═CF2                   4-H       5-Cl    IV.21       3-SCH2CH2CH═CF2                   4-Cl      5-H    IV.22       3-SO2CH2CH2CH═CF2                   4-CN      5-SO2CH2CH2CH═CF2    IV.23       3-(5-Cl-Fur-2-yl)                   4-H       5-SCH2CH2CH═CF2    IV.24       3-(5-Cl-Fur-2-yl)                   4-H       5-SO2CH2CH2CH═CF2    IV.25       3-(Thien-2-yl)                   4-H       5-SCH2CH2CH═CF2    IV.26       3-(Thien-2-yl)                   4-H       5-SO2CH2CH2CH═CF2    __________________________________________________________________________

Examples of compounds of Formula (V) according to the invention are set##STR4## out in Table V.

                                      TABLE V    __________________________________________________________________________    No.       R3          R4         R5    __________________________________________________________________________    V.1       3-CF3       4-H        5-SCH2CH2CH═CF2    V.2       3-Cl        4-CN       5-SCH2CH2CH═CF2    V.3       3-Cl        4-H        5-SCH2CH2CH═CF2    V.4       3-Cl        4-H        5-SO2CH2CH2CH═CF2    V.5       3-H         4-CN       5-SCH2CH2CH═CF2    V.6       3-H         4-CN       5-SO2CH2CH2CH═CF2    V.7       3-H         4-SCH2CH2CH═CF2                              5-CF3    V.8       3-H         4-SOCH2CH2CH═CF2                              5-CF3    V.9       3-H         4-SCH2CH2CH═CF2                              5-CN    V.10       3-NO2       4-H        5-SCH2CH2CH═CF2    V.11       3-SCH2CH2CH═CF2                   4-Cl       5-H    V.12       3-SCH2CH2CH═CF2                   4-CN       5-SCH2CH2CH═CF2    V.13       3-SO2CH2CH2CH═CF2                   4-CN       5-SOCH2CH2CH═CF2    V.14       3-SOCH2CH2CH═CF2                   4-CN       5-SO2CH2CH2CH═CF2    V.15       3-SO2CH2CH2CH═CF2                   4-CN       5-SO2CH2CH2CH═CF2    V.16       3-SCH2CH2CH═CF2                   4-H        5-Cl    __________________________________________________________________________

Examples of compounds of Formula (VI) according to the invention are set##STR5## out in Table VI.

                                      TABLE VI    __________________________________________________________________________    No. R2          R4          R5    __________________________________________________________________________    VI.1        2-SCH2CH2CH═CF2                    4-H         5-H    VI.2        2-SOCH2CH2CH═CF2                    4-H         5-H    VI.3        2-SO2CH2CH2CH═CF2                    4-H         5-H    VI.4        2-SCH2CH2CH═CF2                    4-CF3       5-H    VI.5        2-SO2CH2CH2CH═CF2                    4-CF3       5-H    VI.6        2-SCH2CH2CH═CF2                    4-CH3       5-H    VI.7        2-SCH2CH2CH═CF2                    4-CN        5-H    VI.8        2-SCH2CH2CH═CF2                    4-CONH2     5-H    VI.9        2-SCH2CH2CH═CF2                    4-COOCH2CH3 5-H    VI.10        2-SO2CH2CH2CH═CF2                    4-COOCH2CH3 5-H    VI.11        2-SCH2CH2CH═CF2                    4-COOH      5-H    VI.12        2-SO2CH2CH2CH═CF2                    4-H         5-Br    VI.13        2-SCH2CH2CH═CF2                    4-H         5-Cl    VI.14        2-SO2CH2CH2CH═CF2                    4-H         5-Cl    VI.15        2-SCH2CH2CH═CF2                    4-CH3       5-Cl    VI.16        2-SO2CH2CH2CH═CF2                    4-CH3       5-Cl    VI.17        2-SCH2CH2CH═CF2                    4-H         5-F    VI.18        2-SCH2CH2CH═CF2                    4-H         5-C6H5    VI.19        2-SOCH2CH2CH═CF2                    4-H         5-C6H5    VI.20        2-SO2CH2CH2CH═CF2                    4-H         5-C6H5    VI.21        2-SCH2CH2CH═CF2                    4-H         5-CF3    VI.22        2-SCH2CH2CH═CF2                    4-H         5-CN    VI.23        2-SOCH2CH2CH═CF2                    4-H         5-CN    VI.24        2-SO2CH2CH2CH═CF2                    4-H         5-CN    VI.25        2-SCH2CH2CH═CF2                    4-CH3       5-CN    VI.26        2-SOCH2CH2CH═CF2                    4-CH3       5-CN    VI.27        2-SO2CH2CH2CH═CF2                    4-CH3       5-CN    VI.28        2-SCH2CH2CH═CF2                    4-H         5-COOCH2CH3    VI.29        2-SOCH2CH2CH═CF2                    4-H         5-COOCH2CH3    VI.30        2-SO2CH2CH2CH═CF2                    4-H         5-COOCH2CH3    VI.31        2-SCH2CH2CH═CF2                    4-CF3       5-COOCH2CH3    VI.32        2-SCH2CH2CH═CF2                    4-CH3       5-COOCH3    VI.33        2-SOCH2CH2CH═CF2                    4-CH3       5-COOCH3    VI.34        2-SO2CH2CH2CH═CF2                    4-CH3       5-COOCH3    VI.35        2-SCH2CH2CH═CF2                    4-H         5-COOH    VI.36        2-SCH2CH2CH═CF2                    4-CF3       5-COOH    VI.37        2-SCH2CH2CH═CF2                    4-CH3       5-COOH    VI.38        2-SCH2CH2CH═CF2                    4-CH3       5-CONHSO2CH3    VI.39        2-SCH2CH2CH═CF2                    4-H         5-CONH2    VI.40        2-SCH2CH2CH═CF2                    4-CH3       5-CONH2    VI.41        2-SOCH2CH2CH═CF2                    4-CH3       5-CONH2    IV.42        2-SCH2CH2CH═CF2                    4-H         5-NO2    VI.43        2-SOCH2CH2CH═CF2                    4-H         5-NO2    VI.44        2-SO2CH2CH2CH═CF2                    4-H         5-NO2    VI.45        2-SCH2CH2CH═CF2                    4-H         5-SO2F    VI.46        2-SOCH2CH2CH═CF2                    4-H         5-SO2F    VI.47        2-SCH2CH2CH═CF2                    4-H         5-SO2NH2    VI.48        2-SO2CH2CH2CH═CF2                    4-H         5-SO2NH2    VI.49        2-H         4-SCH2CH2CH═CF2                                5-Br    VI.50        2-H         4-SCH2CH2CH═CF2                                5-C6H5    VI.51        2-H         4-SOCH2CH2CH═CF2                                5-C6H5    VI.52        2-H         4-SCH2CH2CH═CF2                                5-CF3    VI.53        2-H         4-SOCH2CH2CH═CF2                                5-CF3    VI.54        2-H         4-SCH2CH2CH═CF2                                5-Cl    VI.55        2-H         4-SOCH2CH2CH═CF2                                5-Cl    VI.56        2-H         4-SO2CH2CH2CH═CF2                                5-Cl    VI.57        2-H         4-SCH2CH2CH═CF2                                5-CN    VI.58        2-CH3       4-SCH2CH2CH═CF2                                5-CN    VI.59        2-CH3       4-SOCH2CH2CH═CF2                                5-CN    VI.60        2-CH3       4-SO2CH2CH2CH═CF2                                5-CN    VI.61        2-H         4-SCH2CH2CH═CF2                                5-CONH2    VI.62        2-CH3       4-SCH2CH2CH═CF2                                5-CONH2    VI.63        2-H         4-SCH2CH2CH═CF2                                5-COOCH2CH3    VI.64        2-CH3       4-SCH2CH2CH═CF2                                5-COOCH3    VI.65        2-CH3       4-SO2CH2CH2CH═CF2                                5-COOCH3    VI.66        2-H         4-SCH2CH2CH═CF2                                5-COOH    VI.67        2-H         4-SCH2CH2CH═CF2                                5-F    VI.68        2-H         4-SCH2CH2CH═CF2                                5-H    VI.69        2-H         4-SOCH2CH2CH═CF2                                5-H    VI.70        2-H         4-SO2CH2CH2CH═CF2                                5-H    VI.71        2-H         4-SCH2CH2CH═CF2                                5-NO2    VI.72        2-H         4-SCH2CH2CH═CF2                                5-SO2F    VI.73        2-H         4-SCH2CH2CH═CF2                                5-SO2NH2    VI.74        2-H         4-Br        5-SCH2CH2CH═CF2    VI.75        2-H         4-C6H5      5-SCH2CH2CH═CF2    VI.76        2-H         4-CF3       5-SCH2CH2CH═CF2    VI.77        2-H         4-CF3       5-SO2CH2CH2CH═CF2    VI.78        2-H         4-Cl        5-SCH2CH2CH═CF2    VI.79        2-H         4-CN        5-SCH2CH2CH═CF2    VI.80        2-H         4-CN        5-SOCH2CH2CH═CF2    VI.81        2-H         4-CN        5-SO2CH2CH2CH═CF2    VI.82        2-CH3       4-CN        5-SCH2CH2CH═CF2    VI.83        2-H         4-CONH2     5-SCH2CH2CH═CF2    VI.84        2-H         4-CONH2     5-SOCH2CH2CH═CF2    VI.85        2-H         4-CONH2     5-SO2CH2CH2CH═CF2    VI.86        2-CH3       4-CONH2     5-SCH2CH2CH═CF2    VI.87        2-H         4-COOCH2CH3 5-SCH2CH2CH═CF2    VI.88        2-H         4-COOCH2CH3 5-SOCH2CH2CH═CF2    VI.89        2-H         4-COOCH2CH3 5-SO2CH2CH2CH═CF2    VI.90        2-CH3       4-COOCH3    5-SCH2CH2CH═CF2    VI.91        2-H         4-COOH      5-SCH2CH2CH═CF2    VI.92        2-H         4-F         5-SCH2CH2CH═CF2    VI.93        2-H         4-H         5-SCH2CH2CH═CF2    VI.94        2-H         4-H         5-SOCH2CH2CH═CF2    VI.95        2-H         4-H         5-SO2CH2CH2CH═CF2    VI.96        2-H         4-NO2       5-SCH2CH2CH═CF2    VI.97        2-H         4-NO2       5-SOCH2CH2CH═CF2    VI.98        2-H         4-SO2F      5-SCH2CH2CH═CF2    VI.99        2-H         4-SO2NH2    5-SCH2CH2CH═CF2    VI.100        2-Br        4-H         5-SCH2CH2CH═CF2    VI.101        2-C6H5      4-H         5-SCH2CH2CH═CF2    VI.102        2-C6H5      4-H         5-SOCH2CH2CH═CF2    VI.103        2-C6H5      4-H         5-SO2CH2CH2CH═CF2    VI.104        2-CF3       4-H         5-SCH2CH2CH═CF2    VI.105        2-CF3       4-H         5-SO2CH2CH2CH═CF2    VI.106        2-Cl        4-H         5-SCH2CH2CH═CF2    VI.107        2-CN        4-H         5-SCH2CH2CH═CF2    VI.108        2-CN        4-CH3       5-SCH2CH2CH═CF2    VI.109        2-CONH2     4-H         5-SCH2CH2CH═CF2    VI.110        2-CONH2     4-H         5-SOCH2CH2CH═CF2    VI.111        2-CONH2     4-H         5-SO2CH2CH2CH═CF2    VI.112        2-CONH2     4-CH3       5-SO2CH2CH2CH═CF2    VI.113        2-COOCH2CH3 4-H         5-SCH2CH2CH═CF2    VI.114        2-COOCH3    4-CH3       5-SCH2CH2CH═CF2    VI.115        2-COOH      4-H         5-SCH2CH2CH═CF2    VI.116        2-F         4-H         5-SCH2CH2CH═CF2    VI.117        2-F         4-H         5-SOCH2CH2CH═CF2    VI.118        2-NO2       4-H         5-SCH2CH2CH═CF2    VI.119        2-SO2F      4-H         5-SCH2CH2CH═CF2    VI.120        2-SO2NH2    4-H         5-SCH2CH2CH═CF2    __________________________________________________________________________

Examples of compounds of Formula (VII) according to the invention areset ##STR6## out in Table VII.

                                      TABLE VII    __________________________________________________________________________    No. R2          R4          R5    __________________________________________________________________________    VII.1        2-SCH2CH2CH═CF2                    4-H         5-H    VII.2        2-SOCH2CH2CH═CF2                    4-H         5-H    VII.3        2-SO2CH2CH2CH═CF2                    4-H         5-H    VII.4        2-SCH2CH2CH═CF2                    4-CF3       5-H    VII.5        2-SO2CH2CH2CH═CF2                    4-CF3       5-H    VII.6        2-SCH2CH2CH═CF2                    4-CN        5-H    VII.7        2-SCH2CH2CH═CF2                    4-CONH2     5-H    VII.8        2-SCH2CH2CH═CF2                    4-COOCH2CH3 5-H    VII.9        2-SO2CH2CH2CH═CF2                    4-COOCH2CH3 5-H    VII.10        2-SCH2CH2CH═CF2                    4-COOH      5-H    VII.11        2-SCH2CH2CH═CF2                    4-COOCH2CH3 5-Br    VII.12        2-SO2CH2CH2CH═CF2                    4-COOCH2CH3 5-Br    VII.13        2-SCH2CH2CH═CF2                    4-COOH      5-Br    VII.14        2-SCH2CH2CH═CF2                    4-H         5-Br    VII.15        2-SOCH2CH2CH═CF2                    4-H         5-Br    VII.16        2-SO2CH2CH2CH═CF2                    4-H         5-Br    VII.17        2-SCH2CH2CH═CF2                    4-H         5-C6H5    VII.18        2-SOCH2CH2CH═CF2                    4-H         5-C6H5    VII.19        2-SO2CH2CH2CH═CF2                    4-H         5-C6H5    VII.20        2-SCH2CH2CH═CF2                    4-H         5-CF3    VII.21        2-SCH2CH2CH═CF2                    4-H         5-CH3    VII.22        2-SOCH2CH2CH═CF2                    4-H         5-CH3    VII.23        2-SO2CH2CH2CH═CF2                    4-H         5-CH3    VII.24        2-SCH2CH2CH═CF2                    4-H         5-Cl    VII.25        2-SOCH2CH2CH═CF2                    4-H         5-Cl    VII.26        2-SO2CH2CH2CH═CF2                    4-H         5-Cl    VII.27        2-SCH2CH2CH═CF2                    4-CH3       5-Cl    VII.28        2-SO2CH2CH2CH═CF2                    4-CH3       5-Cl    VII.29        2-SCH2CH2CH═CF2                    4-H         5-CN    VII.30        2-SOCH2CH2CH═CF2                    4-H         5-CN    VII.31        2-SO2CH2CH2CH═CF2                    4-H         5-CN    VII.32        2-SCH2CH2CH2CH═CF2                    4-CH3       5-CN    VII.33        2-SOCH2CH2CH═CF2                    4-CH3       5-CN    VII.34        2-SO2CH2CH2CH═CF2                    4-CH3       5-CN    VII.35        2-SCH2CH2CH═CF2                    4-H         5-CONH2    VII.36        2-SCH2CH2CH═CF2                    4-CH3       5-CONH2    VII.37        2-SOCH2CH2CH═CF2                    4-CH3       5-CONH2    VII.38        2-SCH2CH2CH═CF2                    4-H         5-COOCH2CH3    VII.39        2-SOCH2CH2CH═CF2                    4-H         5-COOCH2CH3    VII.40        2-SO2CH2CH2CH═CF2                    4-H         5-COOCH2CH3    VII.41        2-SCH2CH2CH═CF2                    4-CH3       5-COOCH3    VII.42        2-SOCH2CH2CH═CF2                    4-CH3       5-COOCH3    VII.43        2-SO2CH2CH2CH═CF2                    4-CH3       5-COOCH3    VII.44        2-SCH2CH2CH═CF2                    4-H         5-COOH    VII.45        2-SCH2CH2CH═CF2                    4-CH3       5-COOH    VII.46        2-SCH2CH2CH═CF2                    4-H         5-F    VII.47        2-SCH2CH2CH═CF2                    4-H         5-NO2    VII.48        2-SOCH2CH2CH═CF2                    4-H         5-NO2    VII.49        2-SO2CH2CH2CH═CF2                    4-H         5-NO2    VII.50        2-SCH2CH2CH═CF2                    4-H         5-SO2F    VII.51        2-SOCH2CH2CH═CF2                    4-H         5-SO2F    VII.52        2-SCH2CH2CH═CF2                    4-CH3       5-SO2F    VII.53        2-SO2CH2CH2CH═CF2                    4-CH3       5-SO2F    VII.54        2-SCH2CH2CH═CF2                    4-H         5-SO2NH2    VII.55        2-SO2CH2CH2CH═CF2                    4-H         5-SO2NH2    VII.56        2-SCH2CH2CH═CF2                    4-CH3       5-SO2N(CH2CH2)2    VII.57        2-H         4-SCH2CH2CH═CF2                                5-H    VII.58        2-H         4-SOCH2CH2CH═CF2                                5-H    VII.59        2-H         4-SO2CH2CH2CH═CF2                                5-H    VII.60        2-H         4-SCH2CH2CH═CF2                                5-Br    VII.61        2-H         4-SCH2CH2CH═CF2                                5-C6H5    VII.62        2-H         4-SOCH2CH2CH═CF2                                5-C6H5    VII.63        2-H         4-SCH2CH2CH═CF2                                5-CF3    VII.64        2-H         4-SOCH2CH2CH═CF2                                5-CF3    VII.65        2-H         4-SCH2CH2CH═CF2                                5-Cl    VII.66        2-H         4-SOCH2CH2CH═CF2                                5-Cl    VII.67        2-H         4-SO2CH2CH2CH═CF2                                5-Cl    VII.68        2-H         4-SCH2CH2CH═CF2                                5-CN    VII.69        2-CH3       4-SCH2CH2CH═CF2                                5-CN    VII.70        2-CH3       4-SOCH2CH2CH═CF2                                5-CN    VII.71        2-CH3       4-SO2CH2CH2CH═CF2                                5-CN    VII.72        2-H         4-SCH2CH2CH═CF2                                5-CONH2    VII.73        2-CH3       4-SCH2CH2CH═CF2                                5-CONH2    VII.74        2-H         4-SCH2CH2CH═CF2                                5-COOCH2CH3    VII.75        2-CH3       4-SCH2CH2CH═CF2                                5-COOCH3    VII.76        2-CH3       4-SO2CH2CH2CH═CF2                                5-COOCH3    VII.77        2-H         4-SCH2CH2CH═CF2                                5-COOH    VII.78        2-H         4-SCH2CH2CH═CF2                                5-F    VII.79        2-H         4-SCH2CH2CH═CF2                                5-NO2    VII.80        2-H         4-SCH2CH2CH═CF2                                5-SO2F    VII.81        2-H         4-SCH2CH2CH═CF2                                5-SO2NH2    VII.82        2-H         4-H         5-SCH2CH2CH═CF2    VII.83        2-H         4-H         5-SOCH2CH2CH═CF2    VII.84        2-H         4-H         5-SO2CH2CH2CH═CF2    VII.85        2-H         4-Br        5-SCH2CH2CH═CF2    VII.86        2-H         4-C6H5      5-SCH2CH2CH═CF2    VII.87        2-H         4-CF3       5-SCH2CH2CH═CF2    VII.88        2-H         4-CF3       5-SO2CH2CH2CH═CF2    VII.89        2-H         4-Cl        5-SCH2CH2CH═CF2    VII.90        2-H         4-CN        5-SCH2CH2CH═CF2    VII.91        2-H         4-CN        5-SOCH2CH2CH═CF2    VII.92        2-H         4-CN        5-SO2CH2CH2CH═CF2    VII.93        2-CH3       4-CN        5-SCH2CH2CH═CF2    VII.94        2-H         4-CONH2     5-SCH2CH2CH═CF2    VII.95        2-H         4-CONH2     5-SOCH2CH2CH═CF2    VII.96        2-H         4-CONH2     5-SO2CH2CH2CH═CF2    VII.97        2-CH3       4-CONH2     5-SCH2CH2CH═CF2    VII.98        2-H         4-COOCH2CH3 5-SCH2CH2CH═CF2    VII.99        2-H         4-COOCH2CH3 5-SOCH2CH2CH═CF2    VII.100        2-H         4-COOCH2CH5 5-SO2CH2CH2CH═CF2    VII.101        2-CH3       4-COOCH3    5-SCH2CH2CH═CF2    VII.102        2-H         4-COOH      5-SCH2CH2CH═CF2    VII.103        2-H         4-F         5-SCH2CH2CH═CF2    VII.104        2-H         4-NO2       5-SCH2CH2CH═CF2    VII.105        2-H         4-NO2       5-SOCH2CH2CH═CF2    VII.106        2-H         4-SO2F      5-SCH2CH2CH═CF2    VII.107        2-H         4-SO2NH2    5-SCH2CH2CH═CF2    VII.108        2-Br        4-H         5-SCH2CH2CH═CF2    VII.109        2-C6H5      4-H         5-SCH2CH2CH═CF2    VII.110        2-C6H5      4-H         5-SOCH2CH2CH═CF2    VII.111        2-C6H5      4-H         5-SO2CH2CH2CH═CF2    VII.112        2-CF3       4-H         5-SCH2CH2CH═CF2    VII.113        2-CF3       4-H         5-SO2CH2CH2CH═CF2    VII.114        2-Cl        4-H         5-SCH2CH2CH═CF2    VII.115        2-Cl        4-H         5-SOCH2CH2CH═CF2    VII.116        2-Cl        4-H         5-SO2CH2CH2CH═CF2    VII.117        2-CN        4-H         5-SCH2CH2CH═CF2    VII.118        2-CN        4-CH3       5-SCH2CH2CH═CF2    VII.119        2-CONH2     4-H         5-SCH2CH2CH═CF2    VII.120        2-CONH2     4-H         5-SOCH2CH2CH═CF2    VII.121        2-CONH2     4-H         5-SO2CH2CH2CH═CF2    VII.122        2-CONH2     4-CH3       5-SO2CH2CH2CH═CF2    VII.123        2-COOCH2CH3 4-H         5-SCH2CH2CH═CF2    VII.124        2-COOCH3    4-CH3       5-SCH2CH2CH═CF2    VII.125        2-COOH      4-H         5-SCH2CH2CH═CF2    VII.126        2-F         4-H         5-SCH2CH2CH═CF2    VII.127        2-F         4-H         5-SOCH2CH2CH═CF2    VII.128        2-NH2       4-H         5-SCH2CH2CH═CF2    VII.129        2-NO2       4-H         5-SCH2CH2CH═CF2    VII.130        2-O(4-CN--C6H4)                    4-H         5-SCH2CH2CH═CF2    VII.131        2-SO2F      4-H         5-SCH2CH2CH═CF2    VII.132        2-SO2NH2    4-H         5-SCH2CH2CH═CF2    VII.133        2-S-(2)-(5-Cl Thiazole)                    4-H         5-SCH2CH2CH═CF2    __________________________________________________________________________

Examples of compounds of Formula (VIII) according to the invention areset in Table VIII. ##STR7##

                                      TABLE VIII    __________________________________________________________________________    No.  R1        R2          R4          R5    __________________________________________________________________________    VIII.1         1-H       2-SCH2CH2CH═CF2                               4-H         5-H    VIII.2         1-H       2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.3         1-C6H5    2-SCH2CH2CH═CF2                               4-H         5-H    VIII.4         1-C6H5    2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.5         I-CH3     2-SCH2CH2CH═CF2                               4-H         5-H    VIII.6         1-CH3     2-SOCH2CH2CH═CF2                               4-H         5-H    VIII.7         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.8         1-CH2CH2CH═CF2                   2-SCH2CH2CH═CF2                               4-H         5-H    VIII.9         1-CH2CH2CH═CF2                   2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.10         1-CH2CH3  2-SCH2CH2CH═CF2                               4-H         5-H    VIII.11         1-CH2CH3  2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.12         1-CH2CH2CH3                   2-SCH2CH2CH═CF2                               4-H         5-H    VIII.13         I-CH2CH2CH3                   2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.14         1-CH(CH3)2                   2-SCH2CH2CH═CF2                               4-H         5-H    VIII.15         I-CH(CH3)2                   2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.16         1-C(CH3)3 2-SCH2CH2CH═CF2                               4-H         5-H    VIII.17         1-C(CH3)3 2-SO2CH2CH2CH═CF2                               4-H         5-H    VIII.18         1-SO2CH3  2-SCH2CH2CH═CF2                               4-H         5-H    VIII.19         1-H       2-SCH2CH2CH═CF2                               4-C6H5      5-H    VIII.20         1-H       2-SOCH2CH2CH═CF2                               4-C6H5      5-H    VIII.21         1-H       2-SO2CH2CH2CH═CF2                               4-C6H5      5-H    VIII.22         1-CH3     2-SCH2CH2CH═CF2                               4-C6H5      5-H    VIII.23         1-CH3     2-SOCH2CH2CH═CF2                               4-C6H5      5-H    VIII.24         1-CH3     2-SO2CH2CH2CH═CF2                               4-C6H5      5-H    VIII.25         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-Br    VIII.26         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-CF3    VIII.27         1-H       2-SCH2CH2CH═CF2                               4-CH2CH3    5-CH3    VIII.28         1-H       2-SO2CH2CH2CH═CF2                               4-CH2CH3    5-CH3    VIII.29         1-H       2-SCH2CH2CH═CF2                               4-CH3       5-CH3    VIII.30         1-H       2-SO2CH2CH2CH═CF2                               4-CH3       5-CH3    VIII.31         1-CH3     2-SCH2CH2CH═CF2                               4-CH3       5-CH3    VIII.32         1-CH3     2-SO2CH2CH2CH═CF2                               4-CH3       5-CH3    VIII.33         1-CH2CH3  2-SCH2CH2CH═CF2                               4-CH3       5-CH3    VIII.34         1-CH2CH3  2-SO2CH2CH2CH═CF2                               4-CH3       5-CH3    VIII.35         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-CH3    VIII.36         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-CH3    VIII.37         1-CH(CH3)2                   2-SCH2CH2CH═CF2                               4-H         5-CH3    VJII.38         1-CH(CH3)2                   2-SO2CH2CH2CH═CF2                               4-H         5-CH3    VIII.39         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-Cl    VIII.40         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-Cl    VIII.41         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-CN    VIII.42         1-CH3     2-SOCH2CH2CH═CF2                               4-H         5-CN    VIII.43         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-CN    VIII.44         1-CH3     2-SCH2CH2CH═CF2                               4-CH3       5-CN    VIII.45         1-CH3     2-SOCH2CH2CH═CF2                               4-CH3       5-CN    VIII.46         1-CH3     2-SO2CH2CH2CH═CF2                               4-CH3       5-CN    VIII.47         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-CONH2    VIII.48         1-CH3     2-SCH2CH2CH═CF2                               4-CH3       5-CONH2    VIII.49         1-CH3     2-SOCH2CH2CH═CF2                               4-CH3       5-CONH2    VIII.50         1-H       2-SOCH2CH2CH═CF2                               4-H         5-COOCH2CH3    VIII.51         1-H       2-SO2CH2CH2CH═CF2                               4-H         5-COOCH2CH3    VIII.52         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-COOCH2CH3    VIII.53         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-COOCH2CH3    VIII.54         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-COOH    VIII.55         1-CH3     2-SCH2CH2CH═CF2                               4-CH2CH3    5-COOCH3    VIII.56         1-CH3     2-SO2CH2CH2CH═CF2                               4-CH2CH3    5-COOCH3    VIII.57         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-F    VIII.58         1-H       2-SCH2CH2CH═CF2                               4-CH3       5-H    VIII.59         1-H       2-SO2CH2CH2CH═CF2                               4-CH3       5-H    VIII.60         1-CH3     2-SCH2CH2CH═CF2                               4-CH3       5-H    VIII.61         1-CH3     2-SO2CH2CH2CH═CF2                               4-CH3       5-H    VIII.62         1-CH(CH3)2                   2-SCH2CH2CH═CF2                               4-CH3       5-H    VIII.63         1-CH(CH3)2                   2-SO2CH2CH2CH═CF2                               4-CH3       5-H    VIII.64         1-H       2-SCH2CH2CH═CF2                               4-COOCH2CH3 5-H    VIII.65         1-CH3     2-SCH2CH2CH═CF2                               4-COOCH2CH3 5-H    VIII.66         1-CH3     2-SOCH2CH2CH═CF2                               4-COOCH2CH3 5-H    VIII.67         1-CH3     2-SO2CH2CH2CH═CF2                               4-COOCH2CH3 5-H    VIII.68         1-CH3     2-SCH2CH2CH═CF2                               4-COOCH3    5-CH2CH3    VIII.69         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-NO2    VIII.70         1-CH3     2-SOCH2CH2CH═CF2                               4-H         5-NO2    VIII.71         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-NO2    VIII.72         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-SO2F    VIII.73         1-CH3     2-SOCH2CH2CH═CF2                               4-H         5-SO2F    VIll.74         1-CH3     2-SCH2CH2CH═CF2                               4-H         5-SO2NH2    VIII.75         1-CH3     2-SO2CH2CH2CH═CF2                               4-H         5-SO2NH2    VIII.76         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-H    VIII.77         1-CH3     2-H         4-SOCH2CH2CH═CF2                                           5-H    VIII.78         1-CH3     2-H         4-SO2CH2CH2CH═CF2                                           5-H    VIII.79         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-CN    VIII.80         1-CH3     2-CH3       4-SCH2CH2CH═CF2                                           5-CN    VIII.81         1-CH3     2-CH3       4-SOCH2CH2CH═CF2                                           5-CN    VIII.82         1-CH3     2-CH3       4-SO2CH2CH2CH═CF2                                           5-CN    VIII.83         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-C6H5    VIII.84         1-CH3     2-H         4-SOCH2CH2CH═CF2                                           5-C6H5    VIII.85         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-COOCH2CH3    VIII.86         1-CH3     2-CH3       4-SCH2CH2CH═CF2                                           5-COOCH3    VIII.87         1-CH3     2-CH3       4-SO2CH2CH2CH═CF2                                           5-COOCH3    VIII.88         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-COOH    VIII.89         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-CONH2    VIII.90         1-CH3     2-CH3       4-SCH2CH2CH═CF2                                           5-CONH2    VIII.91         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-Cl    VIII.92         1-CH3     2-H         4-SOCH2CH2CH═CF2                                           5-Cl    VIII.93         1-CH3     2-H         4-SO2CH2CH2CH═CF2                                           5-Cl    VIII.94         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-F    VIII.95         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-Br    VIII.96         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-SO2NH2    VIII.97         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-SO2F    VIII.98         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-NO2    VIII.99         1-CH3     2-H         4-SCH2CH2CH═CF2                                           5-CF3    VIII.100         1-CH3     2-H         4-SOCH2CH2CH═CF2                                           5-CF3    VIII.101         1-CH3     2-H         4-H         5-SCH2CH2CH═CF2    VIII.102         1-CH3     2-H         4-H         5-SOCH2CH2CH═CF2    VIII.103         1-CH3     2-H         4-H         5-SO2CH2CH2CH═CF2    VIII.104         1-CH3     2-H         4-CN        5-SCH2CH2CH═CF2    VIII.105         1-CH3     2-H         4-CN        5-SOCH2CH2CH═CF2    VIII.106         1-CH3     2-H         4-CN        5-SO2CH2CH2CH═CF2    VIII.107         1-CH3     2-CH3       4-CN        5-SCH2CH2CH═CF2    VIII.108         1-CH3     2-H         4-C6H5      5-SCH2CH2CH═CF2    VIII.109         1-CH3     2-H         4-COOCH2CH3 5-SCH2CH2CH═CF2    VIII.110         1-CH3     2-H         4-COOCH2CH3 5-SOCH2CH2CH═CF2    VIII.111         1-CH3     2-H         4-COOCH2CH3 5-SO2CH2CH2CH═CF2    VIII.112         1-CH3     2-CH3       4-COOCH3    5-SCH2CH2CH═CF2    VIII.113         1-CH3     2-H         4-COOH      5-SCH2CH2CH═CF2    VIII.114         1-CH3     2-H         4-CONH2     5-SCH2CH2CH═CF2    VIII.115         1-CH3     2-H         4-CONH2     5-SOCH2CH2CH═CF2    VIII.116         1-CH3     2-H         4-CONH2     5-SO2CH2CH2CH═CF2    VIII.117         1-CH3     2-CH3       4-CONH2     5-SCH2CH2CH═CF2    VIII.118         1-CH3     2-H         4-Cl        5-SCH2CH2CH═CF2    VIII.119         1-CH3     2-H         4-F         5-SCH2CH2CH═CF2    VIII.120         1-CH3     2-H         4-Br        5-SCH2CH2CH═CF2    VIII.121         1-CH3     2-H         4-SO2NH2    5-SCH2CH2CH═CF2    VIII.122         1-CH3     2-H         4-SO2F      5-SCH2CH2CH═CF2    VIII.123         1-CH3     2-H         4-NO2       5-SCH2CH2CH═CF2    VIII.124         1-CH3     2-H         4-NO2       5-SOCH2CH2CH═CF2    VIII.125         1-CH3     2-H         4-CF3       5-SCH2CH2CH═CF2    VIII.126         1-CH3     2-H         4-CF3       5-SO2CH2CH2CH═CF2    VIII.127         1-CH3     2-H         4-H         5-SCH2CH2CH═CF2    VIII.128         1-CH3     2-H         4-H         5-SOCH2CH2CH═CF2    VIII.129         1-CH3     2-H         4-H         5-SO2CH2CH2CH═CF2    VIII.130         1-CH3     2-CN        4-H         5-SCH2CH2CH═CF2    VIII.131         1-CH3     2-CN        4-CH3       5-SCH2CH2CH═CF2    VIII.132         1-CH3     2-C6H5      4-H         5-SCH2CH2CH═CF2    VIII.133         1-CH3     2-C6H5      4-H         5-SOCH2CH2CH═CF2    VIII.134         1-CH3     2-C6H5      4-H         5-SO2CH2CH2CH═CF2    VIII.135         1-CH3     2-COOCH2CH3 4-H         5-SCH2CH2CH═CF2    VIII.136         1-CH3     2-COOCH3    4-CH3       5-SCH2CH2CH═CF2    VIII.137         1-CH3     2-COOH      4-H         5-SCH2CH2CH═CF2    VIII.138         1-CH3     2-CONH2     4-H         5-SCH2CH2CH═CF2    VIII.139         1-CH3     2-CONH2     4-H         5-SOCH2CH2CH═CF2    VIII.140         1-CH3     2-CONH2     4-H         5-SO2CH2CH2CH═CF2    VIII.141         1-CH3     2-CONH2     4-CH3       5-SO2CH2CH2CH═CF2    VIII.142         1-CH3     2-Cl        4-H         5-SCH2CH2CH═CF2    VIII.143         1-CH3     2-F         4-H         5-SCH2CH2CH═CF2    VIII.144         1-CH3     2-F         4-H         5-SOCH2CH2CH═CF2    VIII.145         1-CH3     2-Br        4-H         5-SCH2CH2CH═CF2    VIII.146         1-CH3     2-SO2NH2    4-H         5-SCH2CH2CH═CF2    VIII.147         1-CH3     2-SO2F      4-H         5-SCH2CH2CH═CF2    VIII.148         1-CH3     2-NO2       4-H         5-SCH2CH2CH═CF2    VIII.149         1-CH3     2-CF3       4-H         5-SCH2CH2CH═CF2    VIII.150         1-CH3     2-CF3       4-H         5-SO2CH2CH2CH═CF2    VIII.151         1-5 linked                   2-SCH2CH2CH═CF2                               4-H         --CH═CH--CH═CH--    VIII.152         1-5 linked                   2-SO2CH2CH2CH═CF2                               4-H         --CH═CH--CH═CH--    __________________________________________________________________________     Examples of compounds of Formula (IX) according to the invention are set     out in Table IX.     ##STR8##

                                      TABLE IX    __________________________________________________________________________    No. R1      R3          R4          R5    __________________________________________________________________________    IX.1        1-CH3   3-H         4-H         5-SCH2CH2CH═CF2    IX.2        1-CH3   3-H         4-H         5-SOCH2CH2CH═CF2    IX.3        1-CH3   3-H         4-H         5-SO2CH2CH2CH═CF2    IX.4        1-CH3   3-Cl        4-H         5-SCH2CH2CH═CF2    IX.5        1-CH3   3-Cl        4-H         5-SOCH2CH2CH═CF2    IX.6        1-CH3   3-Cl        4-H         5-SO2CH2CH2CH═CF2    IX.7        1-CH3   3-COOC2H5   4-H         5-SCH2CH2CH═CF2    IX.8        1-CH3   3-COOC2H5   4-H         5-SOCH2CH2CH═CF2    IX.9        1-CH3   3-COOC2H5   4-H         5-SO2CH2CH2CH═CF2    IX.10        1-CH3   3-COOH      4-H         5-SCH2CH2CH═CF2    IX.11        1-CH3   3-COOH      4-H         5-SOCH2CH2CH═CF2    IX.12        1-CH3   3-COOH      4-H         5-SO2CH2CH2CH═CF2    IX.13        1-CH3   3-CONH2     4-H         5-SCH2CH2CH═CF2    IX.14        1-CH3   3-CONH2     4-H         5-SOCH2CH2CH═CF2    IX.15        1-CH3   3-CONH2     4-H         5-SO2CH2CH2CH═CF2    IX.16        1-CH3   3-CN        4-H         5-SCH2CH2CH═CF2    IX.17        1-CH3   3-CN        4-H         5-SOCH2CH2CH═CF2    IX.18        1-CH3   3-CN        4-H         5-SO2CH2CH2CH--CF2    IX.19        1-CH3   3-SO2F      4-H         5-SCH2CH2CH═CF2    IX.20        1-CH3   3-SO2F      4-H         5-SOCH2CH2CH--CF2    IX.21        1-CH3   3-SO2F      4-H         5-SO2CH2CH2CH═CF2    IX.22        1-CH3   3-SO2NH2    4-H         5-SCH2CH2CH═CF2    IX.23        1-CH3   3-SO2NH2    4-H         5-SOCH2CH2CH═CF2    IX.24        1-CH3   3-SO2NH2    4-H         5-SO2CH2CH2CH═CF2    IX.25        1-CH3   3-H         4-H         5-SCH2CH2CH═CF2    IX.26        1-CH3   3-H         4-H         5-SOCH2CH2CH═CF2    IX.27        1-CH3   3-H         4-H         5-SO2CH2CH═CF2    IX.28        1-CH3   3-H         4-Cl        5-SCH2CH2CH═CF2    IX.29        1-CH3   3-H         4-Cl        5-SOCH2CH2CH═CF2    IX.30        1-CH3   3-H         4-Cl        5-SO2CH2CH2CH═CF2    IX.31        1-CH3   3-H         4-Br        5-SCH2CH2CH═CF2    IX.32        1-CH3   3-H         4-Br        5-SOCH2CH2CH═CF2    IX.33        1-CH3   3-H         4-Br        5-SO2CH2CH2CH═CF2    IX.34        1-CH3   3-H         4-COOC2H5   5-SCH2CH2CH═CF2    IX.35        1-CH3   3-H         4-COOC2H5   5-SOCH2CH2CH═CF2    IX.36        1-CH3   3-H         4-COOC2H5   5-SO2CH2CH2CH═CF2    IX.37        1-CH3   3-H         4-COOCH(CH3)2                                        5-SCH2CH2CH═CF2    IX.38        1-CH3   3-H         4-COOCH(CH3)2                                        5-SOCH2CH2CH═CH2    IX.39        1-CH3   3-H         4-COOCH(CH3)2                                        5-SO2CH2CH2CH═CF2    IX.40        1-CH3   3-H         4-COOH      5-SCH2CH2CH═CF2    IX.41        1-CH3   3-H         4-COOH      5-SOCH2CH2CH═CF2    IX.42        1-CH3   3-H         4-COOH      5-SO2CH2CH2CH═CF2    IX.43        1-CH3   3-H         4-CONH2     5-SCH2CH2CH═CF2    IX.44        1-CH3   3-H         4-CONH2     5-SOCH2CH2CH═CF2    IX.45        1-CH3   3-H         4-CONH2     5-SO2CH2CH2CH═CF2    IX.46        1-CH3   3-H         4-CN        5-SCH2CH2CH═CF2    IX.47        1-CH3   3-H         4-CN        5-SOCH2CH2CH═CF2    IX.48        1-CH3   3-H         4-CN        5-SO2CH2CH2CH═CF2    IX.49        1-CH3   3-H         4-SO2F      5-SCH2CH2CH═CF2    IX.50        1-CH3   3-H         4-SO2F      5-SOCH2CH2CH═CF2    IX.51        1-CH3   3-H         4-SO2F      5-SO2CH2CH2CH═CF2    IX.52        1-CH3   3-H         4-SO2NH2    5-SCH2CH2CH═CF2    IX.53        1-CH3   3-H         4-SO2NH2    5-SOCH2CH2CH═CF2    IX.54        1-CH3   3-H         4-SO2NH2    5-SO2CH2CH2CH═CF2    IX.55        1-CH3   3-CH3       4-H         5-SCH2CH2CH═CF2    IX.56        1-CH3   3-CH3       4-H         5-SOCH2CH2CH═CF2    IX.57        1-CH3   3-CH3       4-H         5-SO2CH2CH2CH═CF2    IX.58        1-CH3   3-CH3       4-Cl        5-SCH2CH2CH═CF2    IX.59        1-CH3   3-CH3       4-Cl        5-SOCH2CH2CH═CF2    IX.60        1-CH3   3-CH3       4-Cl        5-SO2CH2CH2CH═CF2    IX.61        1-CH3   3-CH3       4-I         5-SCH2CH2CH═CF2    IX.62        1-CH3   3-CH3       4-I         5-SOCH2CH2CH═CF2    IX.63        1-CH3   3-CH3       4-I         5-SO2CH2CH2CH═CF2    IX.64        1-CH3   3-CH3       4-COOC2H5   5-SCH2CH2CH═CF2    IX.65        1-CH3   3-CH3       4-COOC2H5   5-SOCH2CH2CH═CF2    IX.66        1-CH3   3-CH3       4-COOC2H5   5-SO2CH2CH2CH═CF2    IX.67        1-CH3   3-CH3       4-COOH      5-SCH2CH2CH═CF2    IX.68        1-CH3   3-CH3       4-COOH      5-SOCH2CH2CH═CF2    IX.69        1-CH3   3-CH3       4-COOH      5-SO2CH2CH2CH═CF2    IX.70        1-CH3   3-CH3       4-CONH2     5-SCH2CH2CH═CF2    IX.71        1-CH3   3-CH3       4-CONH2     5-SOCH2CH2CH═CF2    IX.72        1-CH3   3-CH3       4-CONH2     5-SO2CH2CH2CH═CF2    IX.73        1-CH3   3-CH3       4-CN        5-SCH2CH2CH═CF2    IX.74        1-CH3   3-CH3       4-CN        5-SOCH2CH2CH═CF2    IX.75        1-CH3   3-CH3       4-CN        5-SO2CH2CH2CH═CF2    IX.76        1-CH3   3-CH3       4-SO2F      5-SCH2CH2CH═CF2    IX.77        1-CH3   3-CH3       4-SO2F      5-SOCH2CH2CH═CF2    IX.78        1-CH3   3-CH3       4-SO2F      5-SO2CH2CH2CH═CF2    IX.79        1-CH3   3-CH3       4-SO2NH2    5-SCH2CH2CH═CF2    IX.80        1-CH3   3-CH3       4-SO2NH2    5-SOCH2CH2CH═CF2    IX.81        1-CH3   3-CH3       4-SO2NH2    5-SO2CH2CH2CH═CF2    IX.82        1-CH3   3-CH3       4-NO2       5-SCH2CH2CH═CF2    IX.83        1-CH3   3-CH3       4-NO2       5-SOCH2CH2CH═CF2    IX.84        1-CH3   3-CH3       4-NO2       5-SO2CH2CH2CH═CF2    IX.85        1-CH3   3-CF3       4-H         5-SCH2CH2CH═CF2    IX.86        1-CH3   3-CF3       4-H         5-SOCH2CH2CH═CF2    IX.87        1-CH3   3-CF3       4-H         5-SO2CH2CH2CH═CF2    IX.88        1-CH3   3-C6H5      4-H         5-SCH2CH2CH═CF2    IX.89        1-CH3   3-C6H5      4-H         5-SOCH2CH2CH═CF2    IX.90        1-CH3   3-C6H5      4-H         5-SO2CH2CH2CH═CF2    IX.91        1-CH3   3-C6H5      4-CN        5-SCH2CH2CH═CF2    IX.92        1-CH3   3-C6H5      4-CN        5-SOCH2CH2CH═CF2    IX.93        1-CH3   3-C6H5      4-CN        5-SO2CH2CH2CH═CF2    IX.94        1-CH3   3-SCH2CH2CH═CF2                            4-CN        5-H    IX.95        1-CH3   3-SOCH2CH2CH═CF2                            4-CN        5-H    IX.96        1-CH3   3-SO2CH2CH2CH═CF2                            4-CN        5-H    IX.97        1-CH3   3-SCH2CH2CH═CF2                            4-H         5-Cl    IX.98        1-CH3   3-SOCH2CH2CH═CF2                            4-H         5-Cl    IX.99        1-CH3   3-SO2CH2CH2CH═CF2                            4-H         5-Cl    IX.100        1-CH3   3-SCH2CH2CH═CF2                            4-H         5-CN    IX.101        1-CH3   3-SOCH2CH2CH═CF2                            4-H         5-CN    IX.102        1-CH3   3-SO2CH2CH2CH═CF2                            4-H         5-CN    IX.103        1-CH3   3-SCH2CH2CH═CF2                            4-H         5-COOC2H5    IX.104        1-CH3   3-SOCH2CH2CH═CF2                            4-H         5-COOC2H5    IX.105        1-CH3   3-SO2CH2CH2CH═CF2                            4-H         5-COOC2H5    IX.106        1-CH3   3-SCH2CH2CH═CF2                            4-H         5-CF3    IX.107        1-CH3   3-SOCH2CH2CH═CF2                            4-H         5-CF3    IX.108        1-CH3   3-SO2CH2CH2CH═CF2                            4-H         5-CF3    IX.109        1-CH2COOH                3-SCH2CH2CH═CF2                            4-H         5-CF3    IX.110        1-CH2COOH                3-SOCH2CH2CH═CF2                            4-H         5-CH3    IX.111        1-CH2COOH                3-SO2CH2CH2CH═CF2                            4-H         5-CH3    IX.112        1-CH2COOC2H5                3-SCH2CH2CH═CF2                            4-H         5-C6H5    IX.113        1-CH2COOC2H5                3-SOCH2CH2CH═CF2                            4-H         5-C6H5    IX.114        1-CH2COOC2H5                3-SO2CH2CH2CH═CF2                            4-H         5-C6H5    IX.115        1-CH2CN 3-SCH2CH2CH═CF2                            4-H         5(2-Thienyl)    IX.116        1-CH2CN 3-SOCH2CH2CH═CF2                            4-H         5(2-Thienyl)    IX.117        1-CH2CN 3-SO2CH2CH2C═CF2                            4-H         5(2-Thienyl)    IX.118        1-C6H5  3-H         4-H         5-SCH2CH2CH═CF2    IX.119        1-C6H5  3-H         4-H         5-SOCH2CH2CH═CF2    IX.120        1-C6H5  3-H         4-H         5-SO2CH2CH2CH═CF2    IX.121        1-C6H5  3-H         4-CN        5-SCH2CH2CH═CF2    IX.122        1-C6H5  3-H         4-CN        5-SOCH2CH2CH═CF2    IX.123        1-C6H5  3-H         4-CN        5-SO2CH2CH2CH═CF2    IX.124        1-C6H5  3-H         4-COOC2H5   5-SCH2CH2CH═CF2    IX.125        1-C6H5  3-H         4-COOC2H5   5-SOCH2CH2CH═CF2    IX.126        1-C6H5  3-H         4-COOC2H5   5-SO2CH2CH2CH═CF2    IX.127        1-C6H5  3-H         4-COOH      5-SCH2CH2CH═CF2    IX.128        1-C6H5  3-H         4-COOH      5-SOCH2CH2CH═CF2    IX.129        1-C6H5  3-H         4-COOH      5-SO2CH2CH2CH═CF2    IX.130        1-C6H5  3-H         4-Cl        5-SCH2CH2CH═CF2    IX.131        1-C6H5  3-H         4-Cl        5-SOCH2CH2CH═CF2    IX.132        1-C6H5  3-H         4-Cl        5-SO2CH2CH2CH═CF2    IX.133        1-C6H5  3-H         4-SO2F      5-SCH2CH2CH═CF2    IX.134        1-C6H5  3-H         4-SO2F      5-SOCH2CH2CH═CF2    IX.135        1-C6H5  3-H         4-SO2F      5-SO2CH2CH2CH═CF2    IX.136        1-C6H5  3-CH3       4-H         5-SCH2CH2CH═CF2    IX.137        1-C6H5  3-CH3       4-H         5-SOCH2CH2CH═CF2    IX.I38        1-C6H5  3-CH3       4-H         5-SO2CH2CH2CH═CF2    IX.139        1-C6H5  3-CH3       4-CN        5-SCH2CH2CH═CF2    IX.140        1-C6H5  3-CH3       4-CN        5-SOCH2CH2CH═CF2    IX.141        1-C6H5  3-CH3       4-CN        5-SO2CH2CH2CH═CF2    IX.142        1-C6H5  3-CH3       4-COOC2H5   5-SCH2CH2CH═CF2    IX.143        1-C6H5  3-CH3       4-COOC2H5   5-SOCH2CH2CH═CF2    IX.144        1-C6H5  3-CH3       4-COOC2H5   5-SO2CH2CH2CH═CF2    IX.145        1-C6H5  3-CH3       4-COOH      5-SCH2CH2CH═CF2    IX.146        1-C6H5  3-CH3       4-COOH      5-SOCH2CH2CH═CF2    IX.147        1-C6H5  3-CH3       4-COOH      5-SO2CH2CH2CH═CF2    IX.148        1-C6H5  3-CH3       4-Cl        5-SCH2CH2CH═CF2    IX.149        1-C6H5  3-CH3       4-Cl        5-SOCH2CH2CH═CF2    IX.150        1-C6H5  3-CH3       4-Cl        5-SO2CH2CH2CH═CF2    IX.151        1-C6H5  3-CH3       4-SO2F      5-SCH2CH2CH═CF2    IX.152        1-C6H5  3-CH3       4-SO2F      5-SOCH2CH2CH═CF2    IX.153        1-C6H5  3-CH3       4-SO2F      5-SO2CH2CH2CH═CF2    IX.154        1-C6H5  3-Cl        4-H         5-SCH2CH2CH═CF2    IX.155        1-C6H5  3-Cl        4-H         5-SOCH2CH2CH═CF2    IX.156        1-C6H5  3-Cl        4-H         5-SO2CH2CH2CH═CF2    IX.157        1-C6H5  3-COOC2H5   4-H         5-SCH2CH2CH═CF2    IX.158        1-C6H5  3-COOC2H5   4-H         5-SOCH2CH2CH═CF2    IX.159        1-C6H5  3-COOC2H5   4-H         5-SO2CH2CH2CH═CF2    IX.160        1-C6H5  3-COOH      4-H         5-SCH2CH2CH═CF2    IX.161        1-C6H5  3-COOH      4-H         5-SOCH2CH2CH═CF2    IX.162        1-C6H5  3-COOH      4-H         5-SO2CH2CH2CH═CF2    IX.163        1-C6H5  3-CONH2     4-H         5-SCH2CH2CH═CF2    IX.164        1-C6H5  3-CONH2     4-H         5-SOCH2CH2CH═CF2    IX.165        1-C6H5  3-CONH2     4-H         5-SO2CH2CH2CH═CF2    IX.166        1-C6H5  3-CN        4-H         5-SCH2CH2CH═CF2    IX.167        1-C6H5  3-CN        4-H         5-SOCH2CH2CH═CF2    IX.168        1-C6H5  3-CN        4-H         5-SO2CH2CH2CH═CF2    IX.169        1-C6H5  3-SO2F      4-H         5-SCH2CH2CH═CF2    IX.170        1-C6H5  3-SO2F      4-H         5-SOCH2CH2CH═CF2    IX.171        1-C6H5  3-SO2F      4-H         5-SO2CH2CH2CH═CF2    IX.172        1-C6H5  3-SO2NH2    4-H         5-SCH2CH2CH═CF2    IX.173        1-C6H5  3-SO2NH2    4-H         5-SOCH2CH2CH═CF2    IX.174        1-C6H5  3-SO2NH2    4-H         5-SO2CH2CH2CH═CF2    IX.175        1-CH3   3-H         4-SCH2CH2CH═CF2                                        5-CN    IX.176        1-CH3   3-H         4-SOCH2CH2CH═CF2                                        5-CN    IX.177        1-CH3   3-H         4-SO2CH2CH2C═CF2                                        5-CN    IX.178        1-CH3   3-H         4-SCH2CH2CH═CF2                                        5-COOC2H5    IX.179        1-CH3   3-H         4-SOCH2CH2CH═CF2                                        5-COOC2H5    IX.180        1-CH3   3-H         4-SO2CH2CH2C═CF2                                        5-COOC2H5    IX.181        1-CH3   3-H         4-SCH2CH2CH═CF2                                        5-CF3    IX.182        1-CH3   3-H         4-SOCH2CH2CH═CF2                                        5-CF3    IX.183        1-CH3   3-H         4-SO2CH2CH2CH═CF2                                        5-CF3    IX.184        1-CH3   3-CN        4-SCH2CH2CH═CF2                                        5-H    IX.185        1-CH3   3-CN        4-SOCH2CH2CH═CF2                                        5-H    IX.186        1-CH3   3-CN        4-SO2CH2CH2CH═CF2                                        5-H    IX.187        1-CH3   3-COOC2H5   4-SCH2CH2CH═CF2                                        5-H    IX.188        1-CH3   3-COOC2H5   4-SOCH2CH2CH═CF2                                        5-H    IX.189        1-CH3   3-COOC2H5   4-SO2CH2CH2CH═CF2                                        5-H    IX.190        1-CH3   3-CF3       4-SCH2CH2CH═CF2                                        5-H    IX.191        1-CH3   3-CF3       4-SOCH2CH2CH═CF2                                        5-H    IX.192        1-CH3   3-CF3       4-SO2CH2CH2CH═CF2                                        5-H    __________________________________________________________________________     Examples of compounds of Formula (X) according to the invention are set     ##STR9##     out in Table X.

                  TABLE X    ______________________________________    No.    R3               R5    ______________________________________    X.1    3-c-C3H5         5-SCH2CH2CH═CF2    X.2    3-C.tbd.CH       5-SCH2CH2CH═CF2    X.3    3-C6H5           5-SCH2CH2CH═CF2    X.4    3-C6H5           5-SOCH2CH2CH═CF2    X.5    3-C6H5           5-SO2CH2CH2CH═CF2    X.6    3-CF2H           5-SCH2CH2CH═CF2    X.7    3-CF3            5-SCH2CH2CH═CF2    X.8    3-CH(CH3)2       5-SCH2CH2CH═CF2    X.9    3-CH═CH2     5-SCH2CH2CH═CF2    X.10   3-CH2Br          5-SCH2CH2CH═CF2    X.11   3-CH2C6H5        5-SCH2CH2CH═CF2    X.12   3-CH2C6H5        5-SOCH2CH2CH═CF2    X.13   3-CH2CF3         5-SCH2CH2CH═CF2    X.14   3-CH2CF3         5-SOCH2CH2CH═CF2    X.15   3-CH2CF3         5-SO2CH2CH2CH═CF2    X.16   3-CH2CH═CH2  5-SCH2CH2CH═CF2    X.17   3-CH2CH2F        5-SCH2CH2CH═CF2    X.18   3-CH2CH3         5-SCH2CH2CH═CF2    X.19   3-CH2CN          5-SCH2CH2CH═CF2    X.20   3-CH2CN          5-SOCH2CH2CH═CF2    X.21   3-CH2CONH2       5-SCH2CH2CH═CF2    X.22   3-CH2COOCH2CH3   5-SCH2CH2CH═CF2    X.23   3-CH2N(CH3)2     5-SCH2CH2CH═CF2    X.24   3-CH2NHCOCH3     5-SCH2CH2CH═CF2    X.25   3-CH2NHCOOCH3    5-SCH2CH2CH═CF2    X.26   3-CH2OCH3        5-SCH2CH2CH═CF2    X.27   3-CH2OCH3        5-SO2CH2CH2CH═CF2    X.28   3-CH2OH          5-SCH2CH2CH═CF2    X.29   3-CH2OH          5-SOCH2CH2CH═CF2    X.30   3-CH2SO2C6H5     5-SCH2CH2CH═CF2    X.31   3-CH2SO2C6H5     5-SO2CH2CH2CH═CF2    X.32   3-CH3            5-SCH2CH2CH═CF2    X.33   3-CH3            5-SOCH2CH2CH═CF2    X.34   3-CH3            5-SO2CH2CH2CH═CF2    X.35   3-COC6H5         5-SCH2CH2CH═CF2    X.36   3-COCH3          5-SCH2CH2CH═CF2    X.37   3-CON(CH3)2      5-SCH2CH2CH═CF2    X.38   3-CONH2          5-SCH2CH2CH═CF2    X.39   3-CONHCH2C6H5    5-SCH2CH2CH═CF2    X.40   3-CONHCH2C6H5    5-SOCH2CH2CH═CF2    X.41   3-CONHCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    X.42   3-CONHCH3        5-SCH2CH2CH═CF2    X.43   3-CONHSO2CH3     5-SCH2CH2CH═CF2    X.44   3-COCC6H5        5-SCH2CH2CH═CF2    X.45   3-COOC6H5        5-SOCH2CH2CH═CF2    X.46   3-COOC6H5        5-SO2CH2CH2CH═CF2    X.47   3-COOCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    X.48   3-COOCH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    X.49   3-COOCH2CH2CH═CF2                            5-SO2CH2CH2CH═CF2    X.50   3-COOCH2CH2F     5-SCH2CH2CH═CF2    X.51   3-COOCH3         5-SCH2CH2CH═CF2    X.52   3-COOH           5-SCH2CH2CH═CF2    X.53   3-COSCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    X.54   3-CSNH2          5-SCH2CH2CH═CF2    X.55   3-H              5-SCH2CH2CH═CF2    X.56   3-H              5-SOCH2CH2CH═CF2    X.57   3-H              5-SO2CH2CH2CH═CF2    X.58   3-N(SO2CH3)2     5-SCH2CH2CH═CF2    X.59   3-NHCH2CH3       5-SCH2CH2CH═CF2    X.60   3-NHCHO          5-SCH2CH2CH═CF2    X.61   3-NHCOOCH3       5-SCH2CH2CH═CF2    X.62   3-NHCOCF3        5-SCH2CH2CH═CF2    X.63   3-NHCOCF3        5-SOCH2CH2CH═CF2    X.64   3-NHCOCH3        5-SCH2CH2CH═CF2    X.65   3-NHCOCH3        5-SO2CH2CH2CH═CF2    X.66   3-NHCSCH2CH3     5-SCH2CH2CH═CF2    X.67   3-NHCSNHCH2CH3   5-SCH2CH2CH═CF2    X.68   3-NHSO2CH3       5-SCH2CH2CH═CF2    X.69   3-OCF2CF2H       5-SCH2CH2CH═CF2    X.70   3-OCF3           5-SCH2CH2CH═CF2    X.71   3-OCF3           5-SOCH2CH2CH═CF2    X.72   3-OCH2C6H5       5-SCH2CH2CH═CF2    X.73   3-OCH2C6H5       5-SO2CH2CH2CH═CF2    X.74   3-OCH2CF3        5-SCH2CH2CH═CF2    X.75   3-OCH2CF3        5-SOCH2CH2CH═CF2    X.76   3-OCH2CF3        5-SO2CH2CH2CH═CF2    X.77   3-OCH2CH═CCl2                            5-SCH2CH2CH═CF2    X.78   3-OCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    X.79   3-OCH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    X.80   3-OCH2CH═CF2 5-SO2H2CH2CH═CF2    X.81   3-OCH2CH2F       5-SCH2CH2CH═CF2    X.82   3-OCH2COOH       5-SCH2CH2CH═CF2    X.83   3-OCH3           5-SCH2CH2CH═CF2    X.84   3-OCOC6H5        5-SCH2CH2CH═CF2    X.85   3-OCOCH3         5-SCH2CH2CH═CF2    X.86   3-OC6H5          5-SCH2CH2CH═CF2    X.87   3-OC6H5          5-SOCH2CH2CH═CF2    X.88   3-OC6H5          5-SO2CH2CH2CH═CF2    X.89   3-OSO2CH3        5-SCH2CH2CH═CF2    X.90   3-0SO2CH3        5-SOCH2CH2CH═CF2    X.91   3-SCF3           5-SCH2CH2CH═CF2    X.92   3-SCH2CH2CH═CF2                            5-C6H5    X.93   3-SOCH2CH2CH═CF2                            5-C6H5    X.94   3-SO2CH2CH2CH═CF2                            5-C6H5    X.95   3-SCH2CH2CH═CF2                            5-CF2H    X.96   3-SCH2CH2CH═CF2                            5-CF3    X.97   3-SCH2CH2CH═CF2                            5-CH2C6H5    X.98   3-SOCH2CH2CH═CF2                            5-CH2C6H5    X.99   3-SCH2CH2CH═CF2                            5-CH2CF3    X.100  3-SCH2CH2CH═CF2                            5-CH2CH2F    X.101  3-SCH2CH2CH═CF2                            5-CH2Cl    X.102  3-SCH2CH2CH═CF2                            5-CH2CN    X.103  3-SCH2CH2CH═CF2                            5-CH2OCH3    X.104  3-SCH2CH2CH═CF2                            5-CH2OH    X.105  3-SCH2CH2CH═CF2                            5-CH3    X.106  3-SO2CH2CH2CH═CF2                            5-CH3    X.107  3-SCH2CH2CH═CF2                            5-Cl    X.108  3-SCH2CH2CH═CF2                            5-CN    X.109  3-SCH2CH2CH═CF2                            5-CON(CH3)2    X.110  3-SCH2CH2CH═CF2                            5-COOCH2CH2CH═CF2    X.111  3-SCH2CH2CH═CF2                            5-COOCH2CH2F    X.112  3-SCH2CH2CH═CF2                            5-COOCH3    X.113  3-SCH2CH2CH═CF2                            5-F    X.114  3-SCH2CH2CH═CF2                            5-H    X.115  3-SCH2CH2CH═CF2                            5-N(SO2CH3)2    X.116  3-SCH2CH2CH═CF2                            5-NHCHO    X.117  3-SCH2CH2CH═CF2                            5-NHCOCF3    X.118  3-SCH2CH2CH═CF2                            5-NHCOOCH3    X.119  3-SCH2CH2CH═CF2                            5-NHSO2CH3    X.120  3-SCH2CH2CH═CF2                            5-NO2    X.121  3-SCH2CH2CH═CF2                            5-OC6H5    X.122  3-SCH2CH2CH═CF2                            5-OCF2H    X.123  3-SCH2CH2CH═CF2                            5-OCF3    X.124  3-SCH2CH2CH═CF2                            5-OCH2CF3    X.125  3-SOCH2CH2CH═CF2                            5-OCH2CF3    X.126  3-SO2CH2CH2CH═CF2                            5-OCH2CF3    X.127  3-SCH2CH2CH═CF2                            5-OCOCH3    X.128  3-SCH2CH2CH═CF2                            5-OSO2CH3    X.129  3-SCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    X.130  3-SOCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    X.131  3-SO2CH2CH2CH═CF2                            5-SCH2CH2CH═CF2    X.132  3-SCH2CH2CH═CF2                            5-SCH3    X.133  3-SCH2CH2CH═CF2                            5-SO2CF3    X.134  3-SOCH2CH2CH═CF2                            5-SO2CH2CH2CH═CF2    X.135  3-SO2CH2CH2CH═CF2                            5-SO2CH2CH2CH═CF2    X.136  3-SCH2CH2CH═CF2                            5-SO2CH3    X.137  3-SO2CH2CH2CH═CF2                            5-SO2CH3    X.138  3-SCH2CH2CH═CF2                            5-SO2N(CH3)2    X.139  3-SCH2CH2CH═CF2                            5-SOCF3    X.140  3-SOCH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    X.141  3-SCH3           5-SCH2CH2CH═CF2    X.142  3-SO2CF3         5-SCH2CH2CH═CF2    X.143  3-SO2CF3         5-SO2CH2CH2CH═CF2    X.144  3-SO2CH3         5-SCH2CH2CH═CF2    X.145  3-SO2N(CH3)2     5-SCH2CH2CH═CF2    X.146  3-SO2NH2         5-SCH2CH2CH═CF2    X.147  3-SO2NHCH3       5-SCH2CH2CH═CF2    X.148  3-SO2NHCH3       5-SO2CH2CH2CH═CF2    X.149  3-SOCF3          5-SCH2CH2CH═CF2    X.150  3-SOCF3          5-SOCH2CH2CH═CF2    X.151  3-SOCH3          5-SCH2CH2CH═CF2    X.152  3-SOCH3          5-SO2CH2CH2CH═CF2    X.153  3-(4-CF3--C6H4)  5-SCH2CH2CH═CF2    X.154  3-(4-CF3--C6H4)  5-SO2CH2CH2CH═CF2    X.155  3-(4-CH3--C6H4)  5-SCH2CH2CH═CF2    X.156  3-(4-CN--C6H4)   5-SCH2CH2CH═CF2    X.157  3-(4-CONH2--C6H4)                            5-SCH2CH2CH═CF2    X.158  3-(4-CONH2--C6H4)                            5-SO2CH2CH2CH═CF2    X.159  3-(4-NO2--C6H4)  5-SCH2CH2CH═CF2    X.160  3-(4-OCH3--C6H4) 5-SCH2CH2CH═CF2    ______________________________________

Examples of compounds of Formula (XI) according to the invention are set##STR10## out in Table XI.

                  TABLE XI    ______________________________________    No.    R3               R5    ______________________________________    XI.1   3-Br             5-SCH2CH2CH═CF2    XI.2   3-c-C5H9         5-SCH2CH2CH═CF2    XI.3   3-C5H9           5-SOCH2CH2CH═CF2    XI.4   3-C.tbd.CH       5-SCH2CH2CH═CF2    XI.5   3-C6H5           5-SCH2CH2CH═CF2    XI.6   3-C6H5           5-SOCH2CH2CH═CF2    XI.7   3-C6H5           5-SO2CH2CH2CH═CF2    XI.8   3-CF2H           5-SCH2CH2CH═CF2    XI.9   3-CF3            5-SCH2CH2CH═CF2    XI.10  3-CH═CH2     5-SCH2CH2CH═CF2    XI.11  3-CH═CHCH3   5-SCH2CH2CH═CF2    XI.12  3-CH═CHCN    5-SCH2CH2CH═CF2    XI.13  3-CH═CHNO2   5-SCH2CH2CH═CF2    XI.14  3-CH═NOCH3   5-SCH2CH2CH═CF2    XI.15  3-CH2(3-CF3--C6H4)                            5-SCH2CH2CH═CF2    XI.16  3-CH2(3-CF3--C6H4)                            5-SCH2CH2CH═CF2    XI.17  3-CH2C6H5        5-SCH2CH2CH═CF2    XI.18  3-CH2C6H5        5-SOCH2CH2CH═CF2    XI.19  3-CH2C6H5        5-SO2CH2CH2CH═CF2    XI.20  3-CH2CF3         5-SCH2CH2CH═CF2    XI.21  3-CH2CF3         5-SOCH2CH2CH═CF2    XI.22  3-CH2CH═CH2  5-SCH2CH2CH═CF2    XI.23  3-CH2CH3         5-SCH2CH2CH═CF2    XI.24  3-CH2CH3         5-SO2CH2CH2CH═CF2    XI.25  3-CH2Cl          5-SCH2CH2CH═CF2    XI.26  3-CH2CN          5-SCH2CH2CH═CF2    XI.27  3-CH2CONH2       5-SCH2CH2CH═CF2    XI.28  3-CH2N(CH3)2     5-SCH2CH2CH═CF2    XI.29  3-CH2NHCOCH3     5-SCH2CH2CH═CF2    XI.30  3-CH2OCH2CH2CH2CH3                            5-SCH2CH2CH═CF2    XI.31  3-CH2OCH2CH2CH3  5-SCH2CH2CH═CF2    XI.32  3-CH2OCH2CH3     5-SCH2CH2CH═CF2    XI.33  3-CH2OCH2CH3     5-SOCH2CWCH═CF2    XI.34  3-CH2OCH3        5-SCH2CH2CH═CF2    XI.35  3-CH2OCH3        5-SOCH2CH2CH═CF2    XI.36  3-CH2OCH3        5-SO2CH2CH2CH═CF2    XI.37  3-CH2OH          5-SCH2CH2CH═CF2    XI.38  3-CH2SCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XI.39  3-CH2SO2C6H5     5-SCH2CH2CH═CF2    XI.40  3-CH3            5-SCH2CH2CH═CF2    XI.41  3-CH3            5-SOCH2CH2CH═CF2    XI.42  3-CH3            5-SO2CH2CH2CH═CF2    XI.43  3-Cl             5-SCH2CH2CH═CF2    XI.44  3-Cl             5-SO2CH2CH2CH═CF2    XI.45  3-CN             5-SCH2CH2CH═CF2    XI.46  3-COC6H5         5-SCH2CH2CH═CF2    XI.47  3-COCH3          5-SCH2CH2CH═CF2    XI.48  3-CON(CH3)2      5-SCH2CH2CH═CF2    XI.49  3-CON(CH3)C2H5   5-SCH2CH2CH═CF2    XI.50  3-CONH2          5-SCH2CH2CH═CF2    XI.51  3-CONHCH2C6H5    5-SCH2CH2CH═CF2    XI.52  3-CONHCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XI.53  3-CONHCH2CH2CH3  5-SCH2CH2CH═CF2    XI.54  3-CONHCH3        5-SCH2CH2CH═CF2    XI.55  3-CONHCH3        5-SOCH2CH2CH═CF2    XI.56  3-CONHCH3        5-SO2CH2CH2CH═CF2    XI.57  3-CONHSO2CH3     5-SCH2CH2CH═CF2    XI.58  3-COOC6H5        5-SCH2CH2CH═CF2    XI.59  3-COOCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XI.60  3-COOCH2CH2F     5-SCH2CH2CH═CF2    XI.61  3-COOCH2CH3      5-SCH2CH2CH═CF2    XI.62  3-COOCH3         5-SCH2CH2CH═CF2    XI.63  3-COOH           5-SCH2CH2CH═CF2    XI.64  3-COSCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XI.65  3-CSNH2          5-SCH2CH2CH═CF2    XI.66  3-F              5-SCH2CH2CH═CF2    XI.67  3-H              5-SCH2CH2CH═CF2    XI.68  3-H              5-SOCH2CH2CH═CF2    XI.69  3-H              5-SO2CH2CH2CH═CF2    XI.70  3-N(SO2CH3)2     5-SCH2CH2CH═CF2    XI.71  3-NHCHO          5-SCH2CH2CH═CF2    XI.72  3-NHCOC2H5       5-SCH2CH2CH═CF2    XI.73  3-NHCOCF3        5-SCH2CH2CH═CF2    XI.74  3-NHCOCH3        5-SCH2CH2CH═CF2    XI.75  3-NHCSCH2CH3     5-SCH2CH2CH═CF2    XI.76  3-NHCSNHCH2CH3   5-SCH2CH2CH═CF2    XI.77  3-NHSO2CH3       5-SCH2CH2CH═CF2    XI.78  3-NO2            5-SCH2CH2CH═CF2    XI.79  3-OC6H5          5-SCH2CH2CH═CF2    XI.80  3-OCF2CF2H       5-SCH2CH2CH═CF2    XI.81  3-OCF2H          5-SCH2CH2CH═CF2    XI.82  3-OCF3           5-SCH2CH2CH═CF2    XI.83  3-OCH2CF3        5-SCH2CH2CH═CF2    XI.84  3-OCH2CF3        5-SOCH2CH2CH═CF2    XI.85  3-OCH2CF3        5-SO2CH2CH2CH═CF2    XI.86  3-OCH2CH═CCl2                            5-SCH2CH2CH═CF2    XI.87  3-OCH3           5-SCH2CH2CH═CF2    XI.88  3-OCOC2H5        5-SCH2CH2CH═CF2    XI.89  3-OCOC6H5        5-SCH2CH2CH═CF2    XI.90  3-OCOCH3         5-SCH2CH2CH═CF2    XI.91  3-OSO2CH3        5-SCH2CH2CH═CF2    XI.92  3-SCF3           5-SCH2CH2CH═CF2    XI.93  3-SCH2CH2CH═CF2                            5-CF3    XI.94  3-SCH2CH2CH═CF2                            5-CH2C6H5    XI.95  3-SCH2CH2CH═CF2                            5-CH2CF3    XI.96  3-SCH2CH2CH═CF2                            5-CH2CH═CH2    XI.97  3-SCH2CH2CH═CF2                            5-CH2CN    XI.98  3-SCH2CH2CH═CF2                            5-CH2CONH2    XI.99  3-SCH2CH2CH═CF2                            5-CH2NHCOCH3    XI.100 3-SCH2CH2CH═CF2                            5-CH2OCH3    XI.101 3-SCH2CH2CH═CF2                            5-CH3    XI.102 3-SCH2CH2CH═CF2                            5-Cl    XI.103 3-SCH2CH2CH═CF2                            5-CN    XI.104 3-SCH2CH2CH═CF2                            5-COOCH3    XI.105 3-SCH2CH2CH═CF2                            5-NHCHO    XI.106 3-SCH2CH2CH═CF2                            5-OC6H5    XI.107 3-SCH2CH2CH═CF2                            5-OCH2CF3    XI.108 3-SCH2CH2CH═CF2                            5-OCH3    XI.109 3-SCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XI.110 3-SCH3           5-SCH2CH2CH═CF2    XI.111 3-SO2C2H5        5-SCH2CH2CH═CF2    XI.112 3-SO2CF3         5-SCH2CH2CH═CF2    XI.113 3-SO2CH2CH2CH═CF2                            5-OCH2CF3    XI.114 3-SO2CH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XI.115 3-SO2CH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    XI.116 3-SO2F           5-SCH2CH2CH═CF2    XI.117 3-SO2N(CH3)2     5-SCH2CH2CH═CF2    XI.118 3-SO2NH2         5-SCH2CH2CH═CF2    XI.119 3-SO2NHCH3       5-SCH2CH2CH═CF2    XI.120 3-SOCF3          5-SCH2CH2CH═CF2    XI.121 3-SOCH2CH2CH═CF2                            5-CH2CN    XI.122 3-SOCH2CH2CH═CF2                            5-OCH2CF3    XI.123 3-SOCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XI.124 3-SOCH3          5-SCH2CH2CH═CF2    XI.125 3-(2-Pyrazinyl)  5-SCH2CH2CH═CF2    XI.126 3-(3-F--C6H4)    5-SCH2CH2CH═CF2    XI.127 3-(3-NO2--C6H4)  5-SCH2CH2CH═CF2    XI.128 3-(3-NO2--C6H4)  5-SOCH2CH2CH═CF2    XI.129 3-(3-NO2--C6H4)  5-SO2CH2CH2CH═CF2    XI.130 3-(4-F--C6H4)    5-SCH2CH2CH═CF2    XI.131 3-(4-F--C6H4)    5-SOCH2CH2CH═CF2    XI.132 3-(4-F--C6H4)    5-SO2CH2CH2CH═CF2    ______________________________________

Examples of compounds of Formula (XII) according to the invention areset ##STR11## out in Table XII.

                  TABLE XII    ______________________________________    No.    R2               R5    ______________________________________    XII.1  2-SCH2CH2CH═CF2                            5-c-C3H5    XII.2  2-SCH2CH2CH═CF2                            5-C.tbd.H    XII.3  2-SCH2CH2CH═CF2                            5-C6H5    XII.4  2-SOCH2CH2CH═CF2                            5-C6H5    XII.5  2-SO2CH2CH2CH═CF2                            5-C6H5    XII.6  2-SCH2CH2CH═CF2                            5-CF2H    XII.7  2-SCH2CH2CH═CF2                            5-CF3    XII.8  2-SCH2CH2CH═CF2                            5-CH(CH3)2    XII.9  2-SO2CH2CH2CH═CF2                            5-CH(CH3)2    XII.10 2-SCH2CH2CH═CF2                            5-CH═CH2    XII.11 2-SCH2CH2CH═CF2                            5-CH2(2,6-di F--C6H3)    XII.12 2-SCH2CH2CH═CF2                            5-CH2(4-NO2--C6H4)    XII.13 2-SO2CH2CH2CH═CF2                            5-CH2(4-NO2--C6H4)    XII.14 2-SOCH2CH2CH═CF2                            5-CH2(4-OCH--C6H4)    XII.15 2-SO2CH2CH2CH═CF2                            5-CH2(4-OCH--C6H4)    XII.16 2-SCH2CH2CH═CF2                            5-CH2Br    XII.17 2-SCH2CH2CH═CF2                            5-CH2C6H5    XII.18 2-SOCH2CH2CH═CF2                            5-CH2C6H5    XII.19 2-SO2CH2CH2CH═CF2                            5-CH2C6H5    XII.20 2-SCH2CH2CH═CF2                            5-CH2CF3    XII.21 2-SOCH2CH2CH═CF2                            5-CH2CF3    XII.22 2-SO2CH2CH2CH═CF2                            5-CH2CF3    XII.23 2-SCH2CH2CH═CF2                            5-CH2CH(CH3)2    XII.24 2-SCH2CH2CH═CF2                            5-CH2CH═H2    XII.25 2-SCH2CH2CH═CF2                            5-CH2CH2CH2CH2CH3    XII.26 2-SOCH2CH2CH═CF2                            5-CH2CH2CH2CH2CH3    XII.27 2-SO2CH2CH2CH═CF2                            5-CH2CH2CH2CH2CH3    XII.28 2-SCH2CH2CH═CF2                            5-CH2CH2CH2CH3    XII.29 2-SOCH2CH2CH═CF2                            5-CH2CH2CH2CH3    XII.30 2-SO2CH2CH2CH═CF2                            5-CH2CH2CH2CH3    XII.31 2-SCH2CH2CH═CF2                            5-CH2CH2CH3    XII.32 2-SOCH2CH2CH═CF2                            5-CH2CH2CH3    XII.33 2-SO2CH2CH2CH═CF2                            5-CH2CH2CH3    XII.34 2-SCH2CH2CH═CF2                            5-CH2CH2F    XII.35 2-SCH2CH2CH═CF2                            5-CH2CH3    XII.36 2-SCH2CH2CH═CF2                            5-CH2CN    XII.37 2-SOCH2CH2CH═CF2                            5-CH2CN    XII.38 2-SCH2CH2CH═CF2                            5-CH2CONH2    XII.39 2-SCH2CH2CH═CF2                            5-CH2COOCH2CH3    XII.40 2-SCH2CH2CH═CF2                            5-CH2N(CH3)2    XII.41 2-SCH2CH2CH═CF2                            5-CH2NHCOCH3    XII.42 2-SCH2CH2CH═CF2                            5-CH2NHCOOCH3    XII.43 2-SCH2CH2CH═CF2                            5-CH2OCH3    XII.44 2-SO2CH2CH2CH═CF2                            5-CH2OCH3    XII.45 2-SCH2CH2CH═CF2                            5-CH2OH    XII.46 2-SOCH2CH2CH═CF2                            5-CH2OH    XII.47 2-SCH2CH2CH═CF2                            5-CH2SO2C6H5    XII.48 2-SO2CH2CH2CH═CF2                            5-CH2SO2C6H5    XII.49 2-SCH2CH2CH═CF2                            5-CH3    XII.50 2-SOCH2CH2CH═CF2                            5-CH3    XII.51 2-SO2CH2CH2CH═CF2                            5-CH3    XII.52 2-SCH2CH2CH═CF2                            5-COC6H5    XII.53 2-SCH2CH2CH═CF2                            5-COCH3    XII.54 2-SCH2CH2CH═CF2                            5-CON(CH3)2    XII.55 2-SCH2CH2CH═CF2                            5-CONH2    XI1.56 2-SCH2CH2CH═CF2                            5-CONHCH2C6H5    XII.57 2-SOCH2CH2CH═CF2                            5-CONHCH2C6H5    XII.58 2-SCH2CH2CH═CF2                            5-CONHCH2CH2CH═CF2    XII.59 2-SCH2CH2CH═CF2                            5-CONHCH3    XII.60 2-SCH2CH2CH═CF2                            5-CONHSO2CH3    XII.61 2-SCH2CH2CH═CF2                            5-COOC6H5    XII.62 2-SOCH2CH2CH═CF2                            5-COOC6H5    XII.63 2-SO2CH2CH2CH═CF2                            5-COOC6H5    XII.64 2-SCH2CH2CH═CF2                            5-COOCH2CH2CH═CF2    XII.65 2-SOCH2CH2CH═CF2                            5-COOCH2CH2CH═CF2    XII.66 2-SO2CH2CH2CH═CF2                            5-COOCH2CH2CH═CF2    XII.67 2-SCH2CH2CH═CF2                            5-COOCH2CH2F    XII.68 2-SCH2CH2CH═CF2                            5-COOCH2CH3    XII.69 2-SCH2CH2CH═CF2                            5-COOCH3    XII.70 2-SCH2CH2CH═CF2                            5-COOH    XII.71 2-SCH2CH2CH═CF2                            5-COSCH2CH2CH═CF2    XII.72 2-SCH2CH2CH═CF2                            5-CSNH2    XII.73 2-SCH2CH2CH═CF2                            5-H    XII.74 2-SOCH2CH2CH═CF2                            5-H    XII.75 2-SO2CH2CH2CH═CF2                            5-H    XII.76 2-SCH2CH2CH═CF2                            5-N(SO2CH3)2    XII.77 2-SCH2CH2CH═CF2                            5-NHCH2CH3    XII.78 2-SCH2CH2CH═CF2                            5-NHCHO    XII.79 2-SCH2CH2CH═CF2                            5-NHCOOCH3    XII.80 2-SCH2CH2CH═CF2                            5-NHCOCF3    XII.81 2-SOCH2CH2CH═CF2                            5-NHCOCF3    XII.82 2-SCH2CH2CH═CF2                            5-NHCOCH3    XII.83 2-SO2CH2CH2CH═CF2                            5-NHCOCH3    XII.84 2-SCH2CH2CH═CF2                            5-NHCSCH2CH3    XII.85 2-SCH2CH2CH═CF2                            5-NHCSNHCH2CH3    XII.86 2-SCH2CH2CH═CF2                            5-NHSO2CH3    XII.87 2-SCH2CH2CH═CF2                            5-OCF2CF2H    XII.88 2-SCH2CH2CH═CF2                            5-OCF3    XII.89 2-SOCH2CH2CH═CF2                            5-OCF3    XII.90 2-SCH2CH2CH══CF2                            5-OCH2C6H5    XII.91 2-SO2CH2CH2CH═CF2                            5-OCH2C6H5    XII.92 2-SCH2CH2CH═CF2                            5-OCH2CF3    XII.93 2-SOCH2CH2CH═CF2                            5-OCH2CF3    XII.94 2-SO2CH2CH2CH═CF2                            5-OCH2CF3    XII.95 2-SCH2CH2CH═CF2                            5-OCH2CH═CCl2    XII.96 2-SCH2CH2CH═CF2                            5-OCH2CH2CH═CF2    XII.97 2-SOCH2CH2CH═CF2                            5-OCH2CH2CH═CF2    XII.98 2-SO2CH2CH2CH═CF2                            5-OCH2CH2CH═CF2    XII.99 2-SCH2CH2CH═CF2                            5-OCH2CH2F    XII.100           2-SCH2CH2CH═CF2                            5-OCH2COOH    XII.101           2-SCH2CH2CH═CF2                            5-OCH3    XII.102           2-SCH2CH2CH═CF2                            5-OCOC6H5    XII.103           2-SCH2CH2CH═CF2                            5-OCOCH3    XII.104           2-SCH2CH2CH═CF2                            5-OC6H5    XII.105           2-SOCH2CH2CH═CF2                            5-OC6H5    XII.106           2-SO2CH2CH2CH═CF2                            5-OC6H5    XII.107           2-SCH2CH2CH═CF2                            5-OSO2CH3    XII.108           2-SOCH2CH2CH═CF2                            5-OSO2CH3    XII.109           2-SCH2CH2CH═CF2                            5-SCF3    XII.110           2-SCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XII.111           2-SCH2CH2CH═CF2                            5-SCH3    XII.112           2-SCH2CH2CH═CF2                            5-SO2CF3    XII.113           2-SO2CH2CH2CH═CF2                            5-SO2CF3    XII.114           2-SCH2CH2CH═CF2                            5-SO2CH2CH2CH═CF2    XII.115           2-SO2CH2CH2CH═CF2                            5-SO2CH2CH2CH═CF2    XII.116           2-SCH2CH2CH═CF2                            5-SO2CH3    XII.117           2-SCH2CH2CH═CF2                            5-SO2N(CH3)2    XII.118           2-SCH2CH2CH═CF2                            5-SO2NH2    XII.119           2-SCH2CH2CH═CF2                            5-SO2NHCH3    XII.120           2-SO2CH2CH2CH═CF2                            5-SO2NHCH3    XII.121           2-SCH2CH2CH═CF2                            5-SOCF3    XII.122           2-SOCH2CH2CH═CF2                            5-SOCF3    XII.123           2-SCH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    XII.124           2-SOCH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    XII.125           2-SO2CH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    XII.126           2-SCH2CH2CH═CF2                            5-SOCH3    XII.127           2-SO2CH2CH2CH═CF2                            5-SOCH3    XII.128           2-SCH2CH2CH═CF2                            5-(2-CH3--C6H4)    XII.129           2-SOCH2CH2CH═CF2                            5-(2-CH3--C6H4)    XII.130           2-SO2CH2CH2CH═CF2                            5-(2-CH3--C6H4)    XII.131           2-SCH2CH2CH═CF2                            5-(2-Furyl)    XII.132           2-SCH2CH2CH═CF2                            5-(2-OCH3--C6H4)    XII.133           2-SCH2CH2CH═CF2                            5-(2-Thiophenyl)    XII.134           2-SCH2CH2CH═CF2                            5-(3-Furyl)    XII.135           2-SCH2CH2CH═C2                            5-(4-CF3--C6H4)    XII.136           2-SO2CH2CH2CH═CF2                            5-(4-CF3--C6H4)    XII.137           2-SCH2CH2CH═CF2                            5-(4-CH3--C6H4)    XII.138           2-SCH2CH2CH═CF2                            5-(4-CN--C6H4)    XII.139           2-SCH2CH2CH═CF2                            5-(4-CONH2--C6H4)    XII.140           2-SO2CH2CH2CH═CF2                            5-(4-CONH2--C6H4)    XII.141           2-SCH2CH2CH═CF2                            5-(4-NO2--C6H4)    XII.142           2-SOCH2CH2CH═CF2                            5-(4-NO2--C6H4)    XII.143           2-SO2CH2CH2CH═CF2                            5-(4-NO2--C6H4)    XII.144           2-SCH2CH2CH═CF2                            5-(4-OCH3--C6H4)    XII.145           2-SOCH2CH2CH═CF2                            5-(4-OCH3--C6H4)    XII.146           2-SO2CH2CH2CH═CF2                            5-(4-OCH3--C6H4)    XII.147           2-SCH2CH2CH═CF2                            5-(4-OH--C6H4)    XII.148           2-SCH2CH2CH═CF2                            5-(4-Pyridinyl)    ______________________________________

Examples of compounds of Formula (XIII) according to the invention are##STR12## set out in Table XIII.

                  TABLE XIII    ______________________________________    No.    R2               R5    ______________________________________    XIII.1 2-SCH2CH2CH═CF2                            5-Br    XIII.2 2-SO2CH2CH2CH═CF2                            5-Br    XIII.3 2-SCH2CH2CH═CF2                            5-C(CH3)3    XIII.4 2-SO2CH2CH2CH═CF2                            5-C(CH3)3    XIII.5 2-SCH2CH2CH═CF2                            5-C(O)C6H5    XIII.6 2-SCH2CH2CH═CF2                            5-c-C3H5    XIII.7 2-SO2CH2CH2CH═CF2                            5-c-C3H5    XIII.8 2-SCH2CH2CH═CF2                            5-C.tbd.CH    XIII.9 2-SCH2CH2CH═CF2                            5-C6H5    XIII.10           2-SOCH2CH2CH═CF2                            5-C6H5    XIII.11           2-SO2CH2CH2CH═CF2                            5-C6H5    XIII.12           2-SCH2CH2CH═CF2                            5-CF2H    XIII.13           2-SOCH2CH2CH═CF2                            5-CF2H    XIII.14           2-SCH2CH2CH═CF2                            5-CF3    XIII.15           2-SO2CH2CH2CH═CF2                            5-CF3    XIII.16           2-SCH2CH2CH═CF2                            5-CH(CH3)2    XIII.17           2-SO2CH2CH2CH═CF2                            5-CH(CH3)2    XIII.18           2-SCH2CH2CH═CF2                            5-CH═H2    XIII.19           2-SCH2CH2CH═CF2                            5-CH2Br    XIII.20           2-SCH2CH2CH═CF2                            5-CH2C6H5    XIII.21           2-SOCH2CH2CH═CF2                            5-CH2C6H5    XIII.22           2-SO2CH2CH2CH═CF2                            5-CH2C6H5    XIII.23           2-SCH2CH2CH═CF2                            5-CH2CF3    XIII.24           2-SCH2CH2CH═CF2                            5-CH2CH2F    XIII.25           2-SOCH2CH2CH═CF2                            5-CH2CH2F    XIII.26           2-SO2CH2CH2CH═CF2                            5-CH2CH2F    XIII.27           2-SCH2CH2CH═CF2                            5-CH2CH3    XIII.28           2-SOCH2CH2CH═CF2                            5-CH2CH3    XIII.29           2-SO2CH2CH2CH═CF2                            5-CH2CH3    XIII.30           2-SCH2CH2CH═CF2                            5-CH2CHCH2    XIII.31           2-SCH2CH2CH═CF2                            5-CH2CN    XIII.32           2-SCH2CH2CH═CF2                            5-CH2CONH2    XIII.33           2-SCH2CH2CH═CF2                            5-CH2COOCH2CH3    XIII.34           2-SCH2CH2CH═CF2                            5-CH2N(CH3)2    XIII.35           2-SCH2CH2CH═CF2                            5-CH2OCH3    XIII.36           2-SOCH2CH2CH═CF2                            5-CH2OCH3    XIII.37           2-SO2CH2CH2CH═CF2                            5-CH2OCH3    XIII.38           2-SCH2CH2CH═CF2                            5-CH2OH    XIII.39           2-SCH2CH2CH═CF2                            5-CH2SO2C6H5    XIII.40           2-SCH2CH2CH═CF2                            5-CH3    XIII.41           2-SOCH2CH2CH═CF2                            5-CH3    XIII.42           2-SO2CH2CH2CH═CF2                            5-CH3    XIII.43           2-SCH2CH2CH═CF2                            5-COCH3    XIII.44           2-SCH2CH2CH═CF2                            5-CON(CH3)2    XIII.45           2-SCH2CH2CH═CF2                            5-CONH2    XIII.46           2-SCH2CH2CH═CF2                            5-CONHCH2C6H5    XIII.47           2-SCH2CH2CH═CF2                            5-CONHCH2CH2CH═CF2    XIII.48           2-SOCH2CH2CH═CF2                            5-CONHCH2CH2CH═CF2    XIII.49           2-SO2CH2CH2CH═CF2                            5-CONHCH2CH2CH═CF2    XIII.50           2-SCH2CH2CH═CF2                            5-CONHCH3    XIII.51           2-SCH2CH2CH═CF2                            5-CONHSO2CH3    XIII.52           2-SO2CH2CH2CH═CF2                            5-CONHSO2CH3    XIII.53           2-SCH2CH2CH═CF2                            5-COOC6H5    XIII.54           2-SOCH2CH2CH═CF2                            5-COOC6H5    XIII.55           2-SCH2CH2CH═CF2                            5-COOCH2CH2CH═CF2    XIII.56           2-SOCH2CH2CH═CF2                            5-COOCH2CH2CH═CF2    XIII.57           2-SO2CH2CH2CH═CF2                            5-COOCH2CH2CH═CF2    XIII.58           2-SCH2CH2CH═CF2                            5-COOCH2CH2F    XIII.59           2-SCH2CH2CH═CF2                            5-COOCH3    XIII.60           2-SCH2CH2CH═CF2                            5-COOH    XIII.61           2-SCH2CH2CH═CF2                            5-COSCH2CH2CH═CF2    XIII.62           2-SCH2CH2CH═CF2                            5-CSNH2    XIII.63           2-SCH2CH2CH═CF2                            5-H    XIII.64           2-SOCH2CH2CH═CF2                            5-H    XIII.65           2-SO2CH2CH2CH═CF2                            5-H    XIII.66           2-SCH2CH2CH═CF2                            5-N(CH3)2    XIII.67           2-SCH2CH2CH═CF2                            5-N(SO2CH3)2    XIII.68           2-SO2CH2CH2CH═CF2                            5-N(SO2CH3)2    XIII.69           2-SCH2CH2CH═CF2                            5-NH2    XIII.70           2-SCH2CH2CH═CF2                            5-NHCH3    XIII.71           2-SOCH2CF2CH═CF2                            5-NHCH3    XIII.72           2-SO2CH2CH2CH═CF2                            5-NHCH3    XIII.73           2-SCH2CH2CH═CF2                            5-NHCHO    XIII.74           2-SOCH2CH2CH═CF2                            5-NHCHO    XIII.75           2-SCH2CH2CH═CF2                            5-NHCOCF3    XIII.76           2-SO2CH2CH2CH═CF2                            5-NHCOCF3    XIII.77           2-SCH2CH2CH═CF2                            5-NHCOCH3    XIII.78           2-SCH2CH2CH═CF2                            5-NHCOOCH3    XIII.79           2-SOCH2CH2CH═CF2                            5-NHCOOCH3    XIII.80           2-SCH2CH2CH═CF2                            5-NHCSCH2CH3    XIII.81           2-SCH2CH2CH═CF2                            5-NHCSNHCH2CH3    XIII.82           2-SCH2CH2CH═CF2                            5-NHSO2CH3    XIII.83           2-SO2CH2CH2CH═CF2                            5-NHSO2CH3    XIII.84           2-SCH2CH2CH═CF2                            5-OC6H5    XIII.85           2-SOCH2CH2CH═CF2                            5-OC6H5    XIII.86           2-SO2CH2CH2CH═CF2                            5-OC6H5    XIII.87           2-SCH2CH2CH═CF2                            5-OCF2CF2H    XIII.88           2-SCH2CH2CH═CF2                            5-OCF3    XIII.89           2-SOCH2CH2CH═CF2                            5-OCF3    XIII.90           2-SO2CH2CH2CH═CF2                            5-OCF3    XIII.91           2-SCH2CH2CH═CF2                            5-OCH2C6H5    XIII.92           2-SCH2CH2CH═CF2                            5-OCH2CF3    XIII.93           2-SOCH2CH2CH═CF2                            5-OCH2CF3    XIII.94           2-SO2CH2CH2CH═CF2                            5-OCH2CF3    XIII.95           2-SCH2CH2CH═CF2                            5-OCH2CH═CCl2    XIII.96           2-SCH2CH2CH═CF2                            5-OCH2CH2CH═CF2    XIII.97           2-SOCH2CH2CH═CF2                            5-OCH2CH2CH═CF2    XIII.98           2-SO2CH2CH2CH═CF2                            5-OCH2CH2CH═CF2    XIII.99           2-SCH2CH2CH═CF2                            5-OCH2CH2F    XIII.100           2-SCH2CH2CH═CF2                            5-OCH2COOCH3    XIII.101           2-SCH2CH2CH═CF2                            5-OCH3    XIII.102           2-SOCH2CH2CH═CF2                            5-OCH3    XIII.103           2-SO2CH2CH2CH═CF2                            5-OCH3    XIII.104           2-SCH2CH2CH═CF2                            5-OCOC6H5    XIII.105           2-SCH2CH2CH═CF2                            5-OCOCH3    XIII.106           2-SCH2CH2CH═CF2                            5-OSO2CH3    XIII.107           2-SOCH2CH2CH═CF2                            5-OSO2CH3    XIII.108           2-SO2CH2CH2CH═CF2                            5-OSO2CH3    XIII.109           2-SCH2CH2CH═CF2                            5-SCF3    XIII.110           2-SCH2CH2CH═CF2                            5-SCH2(3-CF3C6H4)    XIII.111           2-SOCH2CH2CH═CF2                            5-SCH2(3-CF3C6H4)    XIII.112           2-SO2CH2CH2CH═CF2                            5-SCH2(3-CF3C6H4)    XIII.113           2-SCH2CH2CH═CF2                            5-SCH2(4-CF3C6H4)    XIII.114           2-SCH2CH2CH═CF2                            5-SCH2(c-C3H5)    XIII.115           2-SCH2CH2CH═CF2                            5-SCH2C.tbd.CH    XIII.116           2-SCH2CH2CH═CF2                            5-SCH2CH═CH2    XIII.117           2-SCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XIII.118           2-SOCH2CH2CH═CF2                            5-SCH2CH2CH═CF2    XIII.119           2-SCH2CH2CH═CF2                            5-SCH3    XIII.120           2-SOCH2CH2CH═CF2                            5-SCH3    XIII.121           2-SO2CH2CH2CH═CF2                            5-SCH3    XIII.122           2-SCH2CH2CH═CF2                            5-SH    XIII.123           2-SCH2CH2CH═CF2                            5-SO2CH2CH2CH═CF2    XIII.124           2-SO2CH2CH2CH═CF2                            5-SO2CH2CH2CH═CF2    XIII.125           2-SCH2CH2CH═CF2                            5-SO2CH3    XIII.126           2-SO2CH2CH2CH═CF2                            5-SO2CH3    XIII.127           2-SCH2CH2CH═CF2                            5-SO2N(CH3)2    XIII.128           2-SCH2CH2CH═CF2                            5-SO2NH2    XIII.129           2-SCH2CH2CH═CF2                            5-SO2NHCH3    XIII.130           2-SCH2CH2CH═CF2                            5-SOCF3    XIII.131           2-SOCH2CH2CH═CF2                            5-SOCF3    XIII.132           2-SCH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    XIII.133           2-SOCH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    XIII.134           2-SO2CH2CH2CH═CF2                            5-SOCH2CH2CH═CF2    XIII.135           2-SCH2CH2CH═CF2                            5-SOCH3    XIII.136           2-SCH2CH2CH═CF2                            5-(4-CF3--C6H4)    XIII.137           2-SO2CH2CH2CH═CF2                            5-(4-CF3--C6H4)    XIII.138           2-SCH2CH2CH═CF2                            5-(4-CH3--C6H4)    XIII.139           2-SO2CH2CH2CH═CF2                            5-(4-CH3--C6H4)    XIII.140           2-SCH2CH2CH═CF2                            5-(4-CN--C6H4)    XIII.141           2-SOCH2CH2CH═CF2                            5-(4-CN--C6H4)    XIII.142           2-SCH2CH2CH═CF2                            5-(4-CONH2--C6H4)    XIII.143           2-SCH2CH2CH═CF2                            5-(4-H2NSO2--C6H4)    XIII.144           2-SCH2CH2CH═CF2                            5-(4-NO2--C6H4)    XIII.145           2-SCH2CH2CH═CF2                            5-(4-OCH3--C6H4)    XIII.146           2-SOCH2CH2CH═CF2                            5-(4-OCH3--C6H4)    XIII.147           2-SO2CH2CH2CH═CF2                            5-(4-OCH3--C6H4)    ______________________________________

Examples of compounds of Formula (XIV) according to the invention are##STR13## set out in Table XIV.

                  TABLE XIV    ______________________________________    No.         R1          R5    ______________________________________    XIV.1       1-CH3       5-SCH2CH2CH═CF2    ______________________________________

Examples of compounds of Formula (XV) according to the invention are set##STR14## out in Table XV.

                  TABLE XV    ______________________________________    No.     R1             R2      R3    R4    ______________________________________    XV.1    1-SCH2CH2CH═CF2                           2-H     3-H   4-NO2    ______________________________________

Examples of compounds of Formula (XVI) according to the invention areset out in Table XVI. ##STR15##

                                      TABLE XVI    __________________________________________________________________________    No. R2          R3          R4          R5        R6    __________________________________________________________________________    XVI.1        2-Cl        3-H         4-SCH2CH2CH═CF2                                            5-H       6-H    XVI.2        2-F         3-F         4-SCH2CH2CH═CF2                                            5-F       6-F    XVI.3        2-F         3-F         4-SOCH2CH2CH═CF2                                            5-F       6-F    XVI.4        2-F         3-F         4-SO2CH2CH2CH═CF2                                            5-F       6-F    XVI.5        2-H         3-H         4-SCH2CH2CH═CF2                                            5-H       6-H    XVI.6        2-H         3-H         4-SO2CH2CH2CH═CF2                                            5-H       6-H    XVI.7        2-SCH2CH2CH═CF2                    3-CF3       4-H         5-H       6-H    XVI.8        2-SCH2CH2CH═CF2                    3-CN        4-H         5-H       6-H    XVI.9        2-SCH2CH2CH═CF2                    3-CONH2     4-H         5-H       6-H    XVI.10        2-SCH2CH2CH═CF2                    3-COOCH2CH2CH═CF2                                4-H         5-H       6-H    XVI.11        2-SCH2CH2CH═CF2                    3-H         4-H         5-CF3     6-H    XVI.12        2-SO2CH2CH2CH═CF2                    3-H         4-H         5-CF3     6-H    XVI.13        2-SCH2CH2CH═CF2                    3-H         4-H         5-Cl      6-H    XVI.14        2-SO2CH2CH2CH═CF2                    3-H         4-H         5-Cl      6-H    XVI.15        2-SCH2CH2CH═CF2                    3-H         4-H         5-CN      6-H    XVI.16        2-SO2CH2CH2CH═CF2                    3-H         4-H         5-CN      6-H    XVI.17        2-SCH2CH2CH═CF2                    3-H         4-H         5-CONH2   6-H    XVI.18        2-SCH2CH2CH═CF2                    3-H         4-H         5-COOH    6-H    XVI.19        2-SCH2CH2CH═CF2                    3-H         4-H         5-H       6-H    XVI.20        2-SO2CH2CH2CH═CF2                    3-H         4-H         5-H       6-H    XVI.21        2-SCH2CH2CH═CF2                    3-H         4-H         5-NO2     6-H    XVI.22        2-SCH2CH2CH═CF2                    3-H         4-H         5-SCH2CH2CH═CF2                                                      6-H    XVI.23        2-SCH2CH2CH═CF2                    3-H         4-H         5-H       6-F    XVI.24        2-SCH2CH2CH═CF2                    3-NO2       4-H         5-H       6-H    __________________________________________________________________________     Examples of compounds of Formula (XVII) according to the invention are     ##STR16##     set out in Table XVII.

                  TABLE XVII    ______________________________________    No.   R3              R4       R5      R6    ______________________________________    XVII.1          3-SCH2CH2CH═CF2                          4-H      5-H     6-CH3    XVII.2          3-SCH2CH2CH═CF2                          4-H      5-H     6-Cl    XVII.3          3-SCH2CH2CH═CF2                          4-H      5-H     6-OCH3    XVII.4          3-SCH2CH2CH═CF2                          4-H      5-H     6-C6H5    XVII.5          3-SOCH2CH2CH═CF2                          4-H      5-H     6-C6H5    XVII.6          3-SO2CH2CH2CH═CF2                          4-H      5-H     6-C6H5    XVII.7          3-SCH2CH2CH═CF2                         --CH═CH--CH═CH--                                         6-H    ______________________________________

Examples of compounds of Formula (XVIII) according to the invention are##STR17## set out in Table XVIII.

                                      TABLE XVIII    __________________________________________________________________________    No.  R2          R3        R5    R6    __________________________________________________________________________    XVIII.1         2-SCH2CH2CH═CF2                     3-H       --CH═CH--CH═CH--    XVIII.2         2-SOCH2CH2CH═CF2                     3-H       --CH═CH--CH═CH--    XVIII.3         2-SO2CH2CH2CH═CF2                     3-H       --CH═CH--CH═CH--    XVIII.4         2-SCH2CH2CH═CF2                     3-H       --CH═(Cl)CH═CH--    XVIII.5         2-SOCH2CH2CH═CF2                     3-H       --CH═(Cl)CH═CH--    XVIII.6         2-SO2CH2CH2CH═CF2                     3-H       --CH═(Cl)CH═CH--    XVIII.7         2-SCH2CH2CH═CF2                     3-H       5-H   6-H    XVIII.8         2-SOCH2CH2CH═CF2                     3-H       5-H   6-H    XVIII.9         2-SO2CH2CH2CH═CF2                     3-H       5-H   6-H    XVIII.10         2-SCH2CH2CH═CF2                     3-Cl      5-H   6-H    XVIII.11         2-SOCH2CH2CH═CF2                     3-Cl      5-H   6-H    XVIII.12         2-SO2CH2CH2CH═CF2                     3-Cl      5-H   6-H    XVIII.13         2-SCH2CH2CH═CF2                     3-SCH2CH2CH═CF2                               5-H   6-H    XVIII.14         2-SCH2CH2CH═CF2                     3-H       5-H   6-Cl    XVIII.15         2-SOCH2CH2CH═CF2                     3-H       5-H   6-Cl    XVIII.16         2-SO2CH2CH2CH═CF2                     3-H       5-H   6-Cl    __________________________________________________________________________

Examples of compounds of Formula (XIX) according to the invention are##STR18## set out in Table XIX.

                  TABLE XIX    ______________________________________    No.      R4             R5        R6    ______________________________________    XIX.1    4-SCH2CH2CH═CF2                            --CH═CH--CH═CH--    ______________________________________

Examples of compounds of Formula (XX) according to the invention are set##STR19## out in Table XX.

                                      TABLE XX    __________________________________________________________________________    No. R3          R5           R6    __________________________________________________________________________    XX.1        3-SCH2CH2CH═CF2                    5-Br         6-H    XX.2        3-SCH2CH2CH═CF2                    5-c-C3H5     6-H    XX.3        3-SOCH2CH2CH═CF2                    5-c-C3H5     6-H    XX.4        3-SCH2CH2CH═CF2                    5-C6H5       6-CH3    XX.5        3-SOCH2CH2CH═CF2                    5-C6H5       6-CH3    XX.6        3-SO2CH2CH2CH═CF2                    5-C6H5       6-CH3    XX.7        3-SOCH2CH2CH═CF2                    5-C6H5       6-CN    XX.8        3-SCH2CH2CH═CF2                    5-C6H5       6-H    XX.9        3-SO2CH2CH2CH═CF2                    5-C6H5       6-H    XX.10        3-SCH2CH2CH═CF2                    5-(4-F--C6H4)                                 6-H    XX.11        3-SOCH2CH2CH═CF2                    5-(4-F--C6H4)                                 6-H    XX.12        3-SCH2CH2CH═CF2                    5-CF2H       6-CH3    XX.13        3-SCH2CH2CH═CF2                    5-CF3        6-H    XX.14        3-SOCH2CH2CH═CF2                    5-CF3        6-OC6H5    XX.15        3-SCH2CH2CH═CF2                    5-CH(CH3)2   6-H    XX.16        3-SCH2CH2CH═CF2                    5-CH═CH2 6-H    XX.17        3-SCH2CH2CH═CF2                    5-CH═CHCN                                 6-H    XX.18        3-SCH2CH2CH═CF2                    5-CH═CHNO2                                 6-H    XX.19        3-SCH2CH2CH═CF2                    5-CH═NOCH3                                 6-CH3    XX.20        3-SCH2CH2CH═CF2                    5-CH2C.tbd.CH                                 6-H    XX.21        3-SCH2CH2CH═CF2                    5-CH2C6H5    6-H    XX.22        3-SOCH2CH2CH═CF2                    5-CH2C6H5    6-H    XX.23        3-SCH2CH2CH═CF2                    5-CH2CF3     6-H    XX.24        3-SCH2CH2CH═CF2                    5-CH2CH═CH2                                 6-H    XX.25        3-SCH2CH2CH═CF2                    5-CH2CH2CH2CH3                                 6-H    XX.26        3-SO2CH2CH2CH═CF2                    5-CH2CH2CH2CH3                                 6-H    XX.27        3-SCH2CH2CH═CF2                    5-CH2CH2CH3  6-H    XX.28        3-SO2CH2CH2CH═CF2                    5-CH2CH2CH3  6-H    XX.29        3-SCH2CH2CH═CF2                    5-CH2CH2F    6-H    XX.30        3-SCH2CH2CH═CF2                    5-CH2CH3     6-H    XX.31        3-SCH2CH2CH═CF2                    5-CH2CN      6-CH3    XX.32        3-SCH2CH2CH═CF2                    5-CH2CONH2   6-H    XX.33        3-SCH2CH2CH═CF2                    5-CH2N(CH3)2 6-CH3    XX.34        3-SCH2CH2CH═CF2                    5-CH2NHCOCH3 6-H    XX.35        3-SCH2CH2CH═CF2                    5-CH2OCH2CH3 6-H    XX.36        3-SOCH2CH2CH═CF2                    5-CH2OCH2CH3 6-H    XX.37        3-SCH2CH2CH═CF2                    5-CH2OCH3    6-CH3    XX.38        3-SCH2CH2CH═CF2                    5-CH2OH      6-H    XX.39        3-SCH2CH2CH═CF2                    5-CH2SO2C6H5 6-H    XX.40        3-SCH2CH2CH═CF2                    5-CH3        6-CF2H    XX.41        3-SCH2CH2CH═CF2                    5-CH3        6-CH═CH2    XX.42        3-SCH2CH2CH═CF2                    5-CH3        6-CH2CH2F    XX.43        3-SCH2CH2CH═CF2                    5-CH3        6-CH2CN    XX.44        3-SCH2CH2CH═CF2                    5-CH3        6-CH2N(CH3)2    XX.45        3-SCH2CH2CH═CF2                    5-CH3        6-CH2OH    XX.46        3-SCH2CH2CH═CF2                    5-CH3        6-CH3    XX.47        3-SCH2CH2CH═CF2                    5-CH3        6-CONH2    XX.48        3-SCH2CH2CH═CF2                    5-CH3        6-CONHCH3    XX.49        3-SCH2CH2CH═CF2                    5-CH3        6-CONHSO2CH3    XX.50        3-SCH2CH2CH═CF2                    5-CH3        6-COOCH2CH3    XX.51        3-SCH2CH2CH═CF2                    5-CH3        6-COOCH3    XX.52        3-SCH2CH2CH═CF2                    5-CH3        6-H    XX.53        3-SOCH2CH2CH═CF2                    5-CH3        6-H    XX.54        3-SO2CH2CH2CH═CF2                    5-CH3        6-H    XX.55        3-SCH2CH2CH═CF2                    5-CH3        6-NHCHO    XX.56        3-SCH2CH2CH═CF2                    5-CH3        6-NHCOCH3    XX.57        3-SCH2CH2CH═CF2                    5-CH3        6-NHCONH2    XX.58        3-SCH2CH2CH═CF2                    5-CH3        6-OCF2H    XX.59        3-SCH2CH2CH═CF2                    5-CH3        6-OCH2CF3    XX.60        3-SCH2CH2CH═CF2                    5-CH3        6-OCH2CH2F    XX.61        3-SCH2CH2CH═CF2                    5-CH3        6-OCOCH3    XX.62        3-SCH2CH2CH═CF2                    5-CH3        6-OSO2CH3    XX.63        3-SCH2CH2CH═CF2                    5-CH3        6-SO2NH2    XX.64        3-SCH2CH2CH═CF2                    5-CH3        6-SOCH3    XX.65        3-SCH2CH2CH═CF2                    5-CHCl2      6-H    XX.66        3-SCH2CH2CH═CF2                    5-CHO        6-CH3    XX.67        3-SCH2CH2CH═CF2                    5-Cl         6-H    XX.68        3-SO2CH2CH2CH═CF2                    5-Cl         6-H    XX.69        3-SCH2CH2CH═CF2                    5-CN         6-H    XX.70        3-SOCH2CH2CH═CF2                    5-CN         6-H    XX.71        3-SCH2CH2CH═CF2                    5-COCH3      6-H    XX.72        3-SCH2CH2CH═CF2                    5-CON(CH3)2  6-H    XX.73        3-SCH2CH2CH═CF2                    5-CONH2      6-H    XX.74        3-SCH2CH2CH═CF2                    5-CONHCH2C6H5                                 6-H    XX.75        3-SOCH2CH2CH═CF2                    5-CONHCH2CH2CH═CF2                                 6-H    XX.76        3-SCH2CH2CH═CF2                    5-CONHCH3    6-H    XX.77        3-SCH2CH2CH═CF2                    5-CONHSO2CH3 6-CH3    XX.78        3-SO2CH2CH2CH═CF2                    5-COOCH2CH2CH═CF2                                 6-H    XX.79        3-SCH2CH2CH═CF2                    5-COOCH2CH2F 6-H    XX.80        3-SCH2CH2CH═CF2                    5-COOCH2CH3  6-H    XX.81        3-SCH2CH2CH═CF2                    5-COOCH3     6-CH3    XX.82        3-SOCH2CH2CH═CF2                    5-COOCH3     6-H    XX.83        3-SCH2CH2CH═CF2                    5-COOH       6-H    XX.84        3-SOCH2CH2CH═CF2                    5-COOH       6-H    XX.85        3-SCH2CH2CH═CF2                    5-F          6-H    XX.86        3-SCH2CH2CH═CF2                    5-H          6-(1-CH3-cC3H4)    XX.87        3-SCH2CH2CH═CF2                    5-H          6-(4-F--C6H4)    XX.88        3-SO2CH2CH2CH═CF2                    5-H          6-(4-F--C6H4)    XX.89        3-SCH2CH2CH═CF2                    5-H          6-Br    XX.90        3-SCH2CH2CH═CF2                    5-H          6-C(CH3)3    XX.91        3-SCH2CH2CH═CF2                    5-H          6-c-C3H5    XX.92        3-SCH2CH2CH═CF2                    5-H          6-c-C5H9    XX.93        3-SCH2CH2CH═CF2                    5-H          6-COCH    XX.94        3-SCH2CH2CH═CF2                    5-H          6-C6H5    XX.95        3-SOCH2CH2CH═CF2                    5-H          6-C6H5    XX.96        3-SCH2CH2CH═CF2                    5-H          6-CF3    XX.97        3-SO2CH2CH2CH═CF2                    5-H          6-CF3    XX.98        3-SCH2CH2CH═CF2                    5-H          6-CH(CH3)2    XX.99        3-SCH2CH2CH═CF2                    5-H          6-CH═CHCN    XX.100        3-SCH2CH2CH═CF2                    5-H          6-CH═CHNO2    XX.101        3-SCH2CH2CH═CF2                    5-H          6-CH═NOCH3    XX.102        3-SOCH2CH2CH═CF2                    5-H          6-CH2(4-CF3--C6H4)    XX.103        3-SCH2CH2CH═CF2                    5-H          6-CH2C.tbd.CH    XX.104        3-SCH2CH2CH═CF2                    5-H          6-CH2C6H5    XX.105        3-SOCH2CH2CH═CF2                    5-H          6-CH2C6H5    XX.106        3-SCH2CH2CH═CF2                    5-H          6-CH2CF3    XX.107        3-SCH2CH2CH═CF2                    5-H          6-CH2CH═CH2    XX.108        3-SCH2CH2CH═CF2                    5-H          6-CH2CH2CH2CH3    XX.109        3-SCH2CH2CH═CF2                    5-H          6-CH2CH2CH3    XX.110        3-SCH2CH2CH═CF2                    5-H          6-CH2CH3    XX.111        3-SCH2CH2CH═CF2                    5-H          6-CH2CONH2    XX.112        3-SCH2CH2CH═CF2                    5-H          6-CH2NHCOCH3    XX.113        3-SCH2CH2CH═CF2                    5-H          6-CH2OCH2CH3    XX.114        3-SCH2CH2CH═CF2                    5-H          6-CH2OCH3    XX.115        3-SCH2CH2CH═CF2                    5-H          6-CH2SO2C6H5    XX.116        3-SCH2CH2CH═CF2                    5-H          6-CH3    XX.117        3-SOCH2CH2CH═CF2                    5-H          6-CH3    XX.118        3-SO2CH2CH2CH═CF2                    5-H          6-CH3    XX.119        3-SCH2CH2CH═CF2                    5-H          6-CHO    XX.120        3-SCH2CH2CH═CF2                    5-H          6-Cl    XX.121        3-SOCH2CH2CH═CF2                    5-H          6-Cl    XX.122        3-SCH2CH2CH═CF2                    5-H          6-CN    XX.123        3-SCH2CH2CH═CF2                    5-H          6-COCH3    XX.124        3-SCH2CH2CH═CF2                    5-H          6-CON(CH3)2    XX.125        3-SO2CH2CH2CH═CF2                    5-H          6-CON(CH3)C2H5    XX.126        3-SCH2CH2CH═CF2                    5-H          6-CONHCH2C6H5    XX.127        3-SCH2CH2CH═CF2                    5-H          6-CONHCH2CH2CH═CF2    XX.128        3-SCH2CH2CH═CF2                    5-H          6-CONHCH2CH2CH3    XX.129        3-SCH2CH2CH═CF2                    5-H          6-COOC6H5    XX.130        3-SCH2CH2CH═CF2                    5-H          6-COOCH2CH2CH═CF2    XX.131        3-SCH2CH2CH═CF2                    5-H          6-COOCH2CH2F    XX.132        3-SCH2CH2CH═CF2                    5-H          6-COOCH3    XX.133        3-SOCH2CH2CH═CF2                    5-H          6-COOCH3    XX.134        3-SCH2CH2CH═CF2                    5-H          6-COOH    XX.135        3-SO2CH2CH2CH═CF2                    5-H          6-COOH    XX.136        3-SCH2CH2CH═CF2                    5-H          6-F    XX.137        3-SCH2CH2CH═CF2                    5-H          6-H    XX.138        3-SCH2CH2CH═CF2                    5-H          6-NHCH2CH3    XX.139        3-SOCH2CH2CH═CF2                    5-H          6-NHCH2CH3    XX.140        3-SCH2CH2CH═CF2                    5-H          6-NHCOC2H5    XX.141        3-SCH2CH2CH═CF2                    5-H          6-NHCOC6H5    XX.142        3-SCH2CH2CH═CF2                    5-H          6-NHCOCF3    XX.143        3-SCH2CH2CH═CF2                    5-H          6-NHCOCH3    XX.144        3-SCH2CH2CH═CF2                    5-H          6-NHCOOCH3    XX.145        3-SCH2CH2CH═CF2                    5-H          6-NHCSCH2CH3    XX.146        3-SCH2CH2CH═CF2                    5-H          6-NHCSNHCH2CH3    XX.147        3-SCH2CH2CH═CF2                    5-H          6-NHSO2CH3    XX.148        3-SCH2CH2CH═CF2                    5-H          6-NO2    XX.149        3-SCH2CH2CH═CF2                    5-H          6-OC4H9    XX.150        3-SOCH2CH2CH═CF2                    5-H          6-OC5H11    XX.151        3-SCH2CH2CH═CF2                    5-H          6-OC6H5    XX.152        3-SOCH2CH2CH═CF2                    5-H          6-OC6H5    XX.153        3-SCH2CH2CH═CF2                    5-H          6-OCF2CF2H    XX.154        3-SCH2CH2CH═CF2                    5-H          6-OCF3    XX.155        3-SOCH2CH2CH═CF2                    5-H          6-OCF3    XX.156        3-SO2CH2CH2CH═CF2                    5-H          6-OCH(CH3)C2H5    XX.157        3-SCH2CH2CH═CF2                    5-H          6-OCH2(4-Cl--C6H4)    XX.158        3-SO2CH2CH2CH═CF2                    5-H          6-OCH2(4-Cl--C6H4)    XX.159        3-SCH2CH2CH═CF2                    5-H          6-OCH2C6H5    XX.160        3-SCH2CH2CH═CF2                    5-H          6-OCH2CCl═CH2    XX.161        3-SCH2CH2CH═CF2                    5-H          6-OCH2CH═CCl2    XX.162        3-SCH2CH2CH═CF2                    5-H          6-OCH2CH═CH2    XX.163        3-SO2CH2CH2CH═CF2                    5-H          6-OCH2CH═CH2    XX.164        3-SCH2CH2CH═CF2                    5-H          6-OCH2CH2CH3    XX.165        3-SCH2CH2CH═CF2                    5-H          6-OCH2CH2COOCH3    XX.166        3-SOCH2CH2CH═CF2                    5-H          6-OCH2CH2COOCH3    XX.167        3-SCH2CH2CH═CF2                    5-H          6-OCH2CH2CH═CF2    XX.168        3-SCH2CH2CH═CF2                    5-H          6-OCH2CH3    XX.169        3-SCH2CH2CH═CF2                    5-H          6-OCH2COOH    XX.170        3-SCH2CH2CH═CF2                    5-H          6-OCH3    XX.171        3-SOCH2CH2CH═CF2                    5-H          6-OCH3    XX.172        3-SCH2CH2CH═CF2                    5-H          6-OCOC2H5    XX.173        3-SCH2CH2CH═CF2                    5-H          6-OCOC6H5    XX.174        3-SCH2CH2CH═CF2                    5-H          6-OH    XX.175        3-SOCH2CH2CH═CF2                    5-H          6-OH    XX.176        3-SCH2CH2CH═CF2                    5-H          6-SCF3    XX.177        3-SOCH2CH2CH═CF2                    5-H          6-SCF3    XX.178        3-SCH2CH2CH═CF2                    5-H          6-SCH2CH2CH3    XX.179        3-SCH2CH2CH═CF2                    5-H          6-SCH2CH2CH═CF2    XX.180        3-SCH2CH2CH═CF2                    5-H          6-SCH3    XX.181        3-SOCH2CH2CH═CF2                    5-H          6-SCH3    XX.182        3-SCH2CH2CH═CF2                    5-H          6-SO2NHCH3    XX.183        3-SCH2CH2CH═CF2                    5-H          6-SOCF3    XX.184        3-SCH2CH2CH═CF2                    5-H          6-SOCH2CH2CH═CF2    XX.185        3-SCH2CH2CH═CF2                    5-NH2        6-CH3    XX.186        3-SO2CH2CH2CH═CF2                    5-NHCH2CH3   6-C6H5    XX.187        3-SCH2CH2CH═CF2                    5-NHCH2CH3   6-H    XX.188        3-SCH2CH2CH═CF2                    5-NHCHO      6-H    XX.189        3-SCH2CH2CH═CF2                    5-NHCOCF3    6-CH3    XX.190        3-SOCH2CH2CH═CF2                    5-NHCOCH3    6-C6H5    XX.191        3-SCH2CH2CH═CF2                    5-NHCOCH3    6-H    XX.192        3-SCH2CH2CH═CF2                    5-NHCONH2    6-CH3    XX.193        3-SCH2CH2CH═CF2                    5-NHCOOCH3   6-H    XX.194        3-SCH2CH2CH═CF2                    5-NHSO2CH3   6-CH3    XX.195        3-SCH2CH2CH═CF2                    5-NMe2       6-H    XX.196        3-SOCH2CH2CH═CF2                    5-NO2        6-C6H5    XX.197        3-SCH2CH2CH═CF2                    5-NO2        6-H    XX.198        3-SCH2CH2CH═CF2                    5-OC6H5      6-H    XX.199        3-SOCH2CH2CH═CF2                    5-OC6H5      6-H    XX.200        3-SOCH2CH2CH═CF2                    5-OC6H5      6-NHCOCH3    XX.201        3-SCH2CH2CH═CF2                    5-OCF2CF2H   6-CH3    XX.202        3-SCH2CH2CH═CF2                    5-OCF2H      6-H    XX.203        3-SCH2CH2CH═CF2                    5-OCF3       6-H    XX.204        3-SOCH2CH2CH═CF2                    5-OCF3       6-H    XX.205        3-SCH2CH2CH═CF2                    5-OCH(CH3)2  6-H    XX.206        3-SOCH2CH2CH═CF2                    5-OCH(CH3)C2H5                                 6-H    XX.207        3-SCH2CH2CH═CF2                    5-OCH2(4-Cl--C6H4)                                 6-H    XX.208        3-SO2CH2CH2CH═CF2                    5-OCH2(4-Cl--C6H4)                                 6-H    XX.209        3-SCH2CH2CH═CF2                    5-OCH2C6H5   6-H    XX.210        3-SCH2CH2CH═CF2                    5-OCH2CCl═CH2                                 6-H    XX.211        3-SCH2CH2CH═CF2                    5-OCH2CF3    6-H    XX.212        3-SCH2CH2CH═CF2                    5-OCH2CH═CH2                                 6-H    XX.213        3-SO2CH2CH2CH═CF2                    5-OCH2CH2COOCH3                                 6-CH3    XX.214        3-SCH2CH2CH═CF2                    5-OCH2CH2cooch3                                 6-H    XX.215        3-SO2CH2CH2CH═CF2                    5-OCH2CH2COOCH3                                 6-H    XX.216        3-SCH2CH2CH═CF2                    5-OCH2CH2CH═CF2                                 6-H    XX.217        3-SCH2CH2CH═CF2                    5-OCH2CH2F   6-CH3    XX.218        3-SCH2CH2CH═CF2                    5-OCH2CH3    6-H    XX.219        3-SCH2CH2CH═CF2                    5-OCH2COOCH3 6-H    XX.220        3-SCH2CH2CH═CF2                    5-OCH2COOH   6-H    XX.221        3-SCH2CH2CH═CF2                    5-OCH3       6-H    XX.222        3-SCH2CH2CH═CF2                    5-OCOC2H5    6-H    XX.223        3-SOCH2CH2CH═CF2                    5-OCOC6H5    6-H    XX.224        3-SCH2CH2CH═CF2                    5-OCOCH3     6-CH3    XX.225        3-SOCH2CH2CH═CF2                    5-OH         6-C6H5    XX.226        3-SCH2CH2CH═CF2                    5-OH         6-CH3    XX.227        3-SCH2CH2CH═CF2                    5-OH         6-H    XX.228        3-SCH2CH2CH═CF2                    5-OSO2CH3    6-H    XX.229        3-SCH2CH2CH═CF2                    5-SCF3       6-H    XX.230        3-SOCH2CH2CH═CF2                    5-SCF3       6-H    XX.231        3-SCH2CH2CH═CF2                    5-SCH2CH2CH═CF2                                 6-H    XX.232        3-SCH2CH2CH═CF2                    5-SCH2CH2CH3 6-H    XX.233        3-SCH2CH2CH═CF2                    5-SCH2CH2CH═CF2                                 6-H    XX.234        3-SCH2CH2CH═CF2                    5-SCH3       6-H    XX.235        3-SOCH2CH2CH═CF2                    5-SCH3       6-H    XX.236        3-SCH2CH2CH═CF2                    5-SO2NH2     6-CH3    XX.237        3-SCH2CH2CH═CF2                    5-SO2NHCH3   6-H    XX.238        3-SCH2CH2CH═CF2                    5-SOCF3      6-H    XX.239        3-SCH2CH2CH═CF2                    5-SOCH3      6-CH3    XX.240        3-CH3       5-CH3        6-SCH2CH2CH═CF2    XX.241        3-CH3       5-H          6-SCH2CH2CH═CF2    XX.242        3-CH3       5-OC4H9      6-SO2CH2CH2CH═CF2    XX.243        3-CH3       5-SCH2CH2CH═CF2                                 6-CH3    XX.244        3-CH3       5-SCH2CH2CH═CF2                                 6-H    XX.245        3-H         5-CH3        6-SCH2CH2CH═CF2    XX.246        3-H         5-H          6-SCH2CH2CH═CF2    XX.247        3-H         5-SCH2CH2CH═CF2                                 6-CH3    XX.248        3-H         5-SCH2CH2CH═CF2                                 6-H    XX.249        3-H         5-SOCH2CH2CH═CF2                                 6-CH3    XX.250        3-H         5-SO2CH2CH2CH═CF2                                 6-CH3    XX.251        3-SCH2CH2CH═CF2                    --(CH2CH2CH2CH2)--    XX.252        3-SOCH2CH2CH═CF2                    --(CH2CH2CH2CH2)--    XX.253        3-SO2CH2CH2CH═CF2                    --(CH2CH2CH2CH2)--    __________________________________________________________________________

Examples of compounds of Formula (XXI) according to the invention are##STR20## set out in Table XXI.

                  TABLE XXI    ______________________________________    No.       R2               R4       R6    ______________________________________    XXI.1     2-SCH2CH2CH═CF2                               4-H      6-H    ______________________________________

The compounds of formula (I) wherein n is 0 may be prepared by a varietyof methods.

They may be prepared, for example, by the reaction of a correspondingthiol compound of formula (XXIII) and an appropriate difluorobut-1-enealkylating agent of formula (XXIV), where L is a good leaving group.This reaction is preferably conducted in the presence of a mild basesuch as an alkali metal carbonate, for example sodium or potassiumcarbonate, in an inert solvent, at a temperature of from 0° C. to 200°C. Conveniently the reaction may be conducted at the reflux temperatureof a suitable inert solvent, for example acetone, which has a boilingpoint within this range.

In formula (XXIV) the leaving group L is preferably a halogen or anester of sulfonic acid having the formula OSO2Rb, as illustrated byformula (XXV), where Rb is a C1-4 alkyl group or a phenyl groupoptionally substituted with a C1-4 alkyl group. More preferably, L isbromine as shown in formula (XXVI).

The sulfonic ester of formula (XXV) may be prepared by reaction of1,4-dibromo-1,1,2-trifluorobutane with the silver salt of the chosensulfonic acid and debromofluorination of the resulting intermediate,4-toluenesulfonate ester.

In copending International Patent Application No. PCT/GB94/01570, wedisclose a method for preparing the compound of formula (XXVI), namely4bromo-1,1-difluorobut-1-ene in which hydrogen bromide is reacted withcommercially available 4-bromo-1,1,2-trifluorobut-1-ene in an inertsolvent to give 1,4-dibromo-1,1,2-trifluorobutane. This intermediate canthen be treated with a debromofluorinating agent in a suitable solvent,for example acetone or water, to give the compound of formula (XXVI).

It will be appreciated by those skilled in the art that compounds ofFormula (XXIII) may exist in tautomeric equilibrium between theequivalent mercapto and thione forms. For the sake of convenience, thesecompounds are referred to herein in their mercapto form unless otherwisestated

Compounds of Formula (XXIII) are commercially available or may beprepared from commercially available precursors by standard procedureswell known in the art.

Alternatively, the compounds of formula (I) may be prepared by reactinga corresponding compound of formula (XXVII), where L is again a goodleaving group, with a mercapto compound of formula (XXVIII), underconditions well known in the art for such displacement reactions.Preferably, L is halogen or a nitro group. Conveniently the reaction maybe carried out using a two phase solvent system, such aswater/dichloromethane, in the presence of a phase transfer catalyst, forexample tetra-n-butyl ammonium bromide, at ambient temperature under anitrogen atmosphere.

The mercapto compound of formula (XXVIII) is conveniently reacted in theform of its S-acetyl or its isothiouronium hydrogen bromide salt, whichcompounds are readily hydrolysed to the mercapto compound of formula(XXVIII).

The compounds of formula (I) may also be prepared from the correspondingamino compound of formula (XXIX), which can be diazotised, for examplewith an alkylnitrite, such as tert butyl nitrite, in the presence of thedisulfide of formula (XXX), in a suitable solvent, such asdichloromethane or acetonitrile.

The compounds of formula (I) where n is 1 or 2, may be prepared byoxidising the correspondingly substituted compound of formula (I) when nis 0, using conventional methods, for example by treatment with asuitable oxidising agent in an inert organic solvent. In general,oxidation of a compound of Formula (I) with one equivalent of a suitableoxidising agent provides the corresponding compound wherein n is 1, andoxidation using two equivalents of the oxidising agent provides thecorresponding compound wherein n is 2. Suitable oxidising agents includeorganic and inorganic peroxides such as peroxy carboxylic acids, ortheir salts, for example, meta-chloroperbenzoic acid, perbenzoic acid,magnesium monoperoxy-phthalic acid or potassium peroxymono-sulfate.

Thus, according to a further aspect of the present invention there isprovided a process for the preparation of compounds of formula (I) wheren is 1 or 2, which comprises oxidation of the correspondinglysubstituted compound of formula (I) when n is 0.

As well as the compounds of formula (I) being prepared from thecorresponding substituted compounds of formula (XXIII), (XXVII) or(XXIX), it will be appreciated that subsequent functional grouptransformations may be carried out using known chemistry to obtain therequired ring substitution. Examples of such functional grouptransformations include the reduction of nitro groups to amine groups,halogenation, e.g. Chlorination, hydrolysis of an ester to the acid,oxidation of an alcohol to the acid, salt formation.

Various further preferred features and embodiments of the presentinvention will now be described in further detail with reference to thefollowing illustrative examples in which percentages are by weight andthe following abbreviations are used: mp=melting point; bp=boilingpoint; g=grammes; gc=gas chromatography; NMR=nuclear magnetic resonance;s=singlet; d=doublet; dd=double doublet; t=triplet; q=quartet;m=multiplet; br=broad; M=mole; mM=millimoles; CDCl₃ =deuteriochloroformChemical shifts (δ) are measured in parts per million fromtetramethylsilane. CDCl₃ was used as solvent for NMR spectra unlessotherwise stated. M⁺ =molecular ion as determined by mass spectrometry;FAB=fast atom bombardment; tlc=thin layer chromatography.

The synthesis of a number of intermediate compounds of use in thepreparation of compounds according to the invention is given below. Someof these compounds are known in the art.

PREPARATION 1

This illustrates a 3-step preparation of 4-bromo-4,4-difluorobutylmethanesulfonate.

Step 1: 4-bromo-4,4-difluorobutanoic acid.

To a stirred solution of acrylic acid (1.44 g) and acetonitrile (80 cm³)was added sodium dithionite (4.18 g), sodium bicarbonate (2.01 g), water(20 cm³) and finally dibromodifluoromethane (5 cm³). The biphasicmixture was stirred at the ambient temperature with the inorganic saltsgradually dissolving. GC analysis after 4 hours indicated completeconsumption of acrylic acid. The aqueous phase was saturated with solidsodium chloride. The organic phase was separated, dried over magnesiumsulfate, filtered and evaporated under reduced pressure to give a paleyellow oil with a small amount of a white solid. This mixture was takenup in ethyl acetate, filtered and solvent evaporated under reducedpressure to give a pale yellow oil (2.54 g). ¹ H NMR (DMSO-d₆): δ2.45(2H,t); 2.65(2H,m).

Step 2: 4-bromo-4,4-difluorobutanol.

Under an atmosphere of nitrogen, a solution of lithium aluminium hydridein diethylether (5 cm³, 5 mM) was cooled to 0° C. Maintaining thistemperature, 4-bromo-4,4-difluorobutanoic acid (1 g) dissolved in drydiethylether (5 cm³) was added dropwise with stirring. After an hour at0° C. the reaction mixture was cautiously quenched by the addition of 2Mhydrochloric acid. The organic phase was separated, washed withsaturated sodium bicarbonate solution, dried over magnesium sulfate,filtered and evaporated under reduced pressure to give a colourless oil(0.57 g). ¹ H NMR: δ 1.82-1.96(2H,m); 2.40-2.60 (2H,m); 3.74(2H,t).

Step 3: 4-bromo-4,4-difluorobutyl methanesulfonate.

A stirred solution of 4-bromo-4,4-difluorobutanol (0.57 g) in drydiethylether (5 cm³) was cooled to 0° C. Maintaining this temperature,triethylamine (1.7 cm³) was added. After ten minutes methanesulfonylchloride (0.3 cm³) was added and the mixture stirred for a further hourat 0° C. The reaction mixture was poured into 2M hydrochloric acid (2cm³) and diethylether (20 cm³). The organic phase was separated, washedwith saturated brine, then passed through a plug of silica gel elutingwith further diethylether. The diethylether fractions were evaporatedunder reduced pressure to give a light yellow oil (0.705 g). ¹ H NMR: δ2.04-2.18(2H,m); 2.46-2.64(2H,m); 3.04(3H,s); 4.32(2H,t).

PREPARATION 2

This illustrates a 3-step preparation of the 4,4-difluorobut-3-enylester of 4-methylbenzenesulfonic acid from commercially available4-bromo-1,1,2-trifluorobut-1-ene.

Step 1: Preparation of 1,4-dibromo-1,1,2-trifluorobutane.

4-Bromo-1,1,2-trifluorobut-1-ene (Fluorochem Ltd) (240 g) was washedwith water (300 cm³) and then with brine (300 cm³) and dried (MgSO₄)before use. Benzoyl peroxide (ca. 0.7 g) was added in one portion andhydrogen bromide gas was bubbled through the mixture at such a rate thatthe reaction temperature was maintained at 30 to 40° C. After 2 hours,gc of a sample of the reaction mixture showed that little startingmaterial remained. The reaction mixture was washed with water (300 cm³),then with saturated sodium bicarbonate solution and then again withwater (300 cm³), dried (MgSO₄), and filtered to give a pale yellow oil(296.7 g) identified as 1,4-dibromo-1,1,2-trifluorobutane. The materialwas shown by gc analysis to be greater than 98% pure. ¹ H NMR: δ2.38(2H,m); 3.57(2H,m); 4.90(1H,m).

Step 2: Preparation of 4-bromo-3,4,4-trifluorobutyl4-methyl-benzenesulfonate

The product from Step 1 (1 g) was added dropwise to a stirred suspensionof silver tosylate (1.03 g) in acetonitrile (10 cm³) at ambienttemperature, protected from the light. The reaction was then heatedunder reflux for 24 hours after which gc analysis indicated completeconsumption of starting material. The reaction mixture was cooled to theambient temperature and the precipitate was filtered off and washed withethyl acetate. The filtrate and ethyl acetate washings were combined andwashed with water and the aqueous layer extracted with ethyl acetate.The combined ethyl acetate layers were washed with water and brine,dried over magnesium sulfate and evaporated under reduced pressure togive a brown oil (1.21 g). GC analysis showed this material to be >99%pure. ¹ H NMR: δ 2.20(2H,m); 2.46(3H,s); 4.19(2H,m); 4.74(1H,m);7.38(2H,d); 7.80(2H,d).

Step 3: Preparation of 4,4difluorobut-3-en1 4-methyl-benzenesulfonate

To a stirred suspension of powdered zinc (1.41 g) and iodine (one grain,catalytic) in methanol (3 cm³) was added a solution of4-bromo-3,4,4-difluorobutyl p-tolylsulfonate (0.71 g) in methanol (2cm³). The reaction mixture was heated under reflux for 21/2 hours afterwhich gc analysis indicated complete consumption of starting material.The organic phase was pipetted from the zinc suspension and the zinc waswashed with 3 portions of ethyl acetate. The combined ethyl acetateportions were washed with 2M hydrochloric acid, dried over magnesiumsulfate and evaporated under reduced pressure to give a brown liquid(0.47 g). GC analysis showed this material to be >99% pure. ¹ H, NMR: δ2.35(2H,m); 2.46(3H,s); 4.01(2H,m); 4.15(1H,m); 7.38(2H,d); 7.79(2H,d).

PREPARATION 3

This illustrates a preparation of 4-bromo-1,1-difluorobut-1-ene from1,4-dibromo-1,1,2-trifluorobutane.

Zinc powder (0.88 g) was added to a stirred solution of1,4-dibromo-1,1,2-trifluorobutane (1.38 g) in acetone (6 cm³) containingwater (1 drop), under an atmosphere of nitrogen. After 45 minutes, gcanalysis showed that a large proportion of the starting material hadbeen consumed. The mixture was then added to more zinc powder (3 g) inacetone containing a trace of water, which had been preheated to 55° C.After a further 20 minutes at this temperature, gc analysis indicatedthat all of the starting material had been consumed, showing that thede-bromofluorination reaction had initiated. More starting material(12.34 g) was then added to the reaction over a period of 75 minuteswhile the reaction mixture was kept at 55° C. Heating was then continuedfor a further 95 minutes. GC analysis of a sample indicated that about3% of the starting dibromo compound remained unchanged. Further zincpowder (0.16 g) was added and heating, continued until gc analysisshowed all the starting material had been consumed. The acetone solutionwas decanted from the zinc residues to give a solution of4-bromo-1,1-difluorobut-1-ene suitable for use in further chemicalreactions.

PREPARATION 4

This illustrates a preparation of 4,4-difluorobut-3-enyl thioacetate.

Potassium thioacetate (1.98 g), 4-bromo-1,1-difluorobut-1-ene (3.0 g)and tetra-n-butylammonium bromide (0.3 g, catalyst) were stirred at theambient temperature under nitrogen for 5 hours and stored for 18 hours.The mixture was distilled using a Kugelrohr apparatus to give4,4-difluorobut-3-enyl thioacetate as a colourless liquid (1.12 g); ¹ HNMR: δ 2.25(2H,m); 2.30(3H,s); 2.90(2H,t); 4.20(1H,m); (bp 115° C. at120 mmHg).

PREPARATION 5

This illustrates a preparation of 4,4-difluorobut-3-enylisothiouronium4-methyl-benzenesulfonate salt.

Thiourea (0.29 g) and 4,4-difluorobut-3-enyl 4-methyl-benzenesulfonate(1 g) were heated together under reflux in ethanol (20 cm³) for 24hours. The reaction mixture was cooled and the solvent evaporated underreduced pressure to give an oil which slowly crystallised. Triturationwith hexane gave (4,4-difluorobut-3-enylthiourea as its4-methyl-benzenesulfonate salt (1.14 g). MH⁺ (FAB)=167; ¹ H NMR(DMSO-d₆): δ 2.48(3H,s); 2.46-2.58(2H,m); 3.42(2H,t); 4.66-4.84(1H,m);7.32(2H,d); 7.68(2H,d); 9.10-9.40(3H,br)

PREPARATION 6

This illustrates a preparation of 4,4-difluorobut-3-enylisothiouroniumhydrobromide.

Thiourea (18.5 g) was added to a solution of4-bromo-1,1-difluorobut-1-ene (41.5 g) in ethanol (150 cm³) and heatedto reflux with stirring for 18 h. The reaction mixture was cooled toambient temperature and evaporated under reduced pressure. The waxysolid obtained was washed with diethyl ether, filtered, washed withfurther diethyl ether and sucked to dryness to give the required productas a colourless solid, (57 g). MH⁺ =167; ¹ H NMR(DMSO-d₆): δ 2.20(2H,m);3.20(2H,t); 4.50(1H,m); 8.95(4H,broad signal).

The N-methyl derivative of the foregoing intermediate was prepared bythe above procedure but using N-methyl thiourea in place of thiourea. Ithad MH⁺ =181; ¹ H NMR(DMSO-d₆): δ 2.45-2.55(2H,m); 3.0-3.05(3H,d);3.4-3.5(2H,t); 4.30-4.45(1H,m); (m.p. 74-77.2° C.).

PREPARATION 7

This illustrates a preparation of bis-(4,4-difluorobut-3-enyl)disulfide.

A solution of sodium disulfide (previously prepared from sodium sulfidenonahydrate (53 g) and sulfur (7.0 g) in ethanol (250 cm³)) was added to1-bromo-4,4-difluorobut-3-ene (50 g) in ethanol (100 cm³). The mixturewas gradually heated and stirred under reflux for 2 hours, then cooledand evaporated under reduced pressure. The residue was extracted withdiethyl ether, the organic phase filtered to remove sodium bromide andthe ether evaporated under reduced pressure to give a liquid which wasdistilled at 16 mm Hg, bp 120° C. to give thebis-(4,4-difluorobut-3-enyl)disulfide (24 g) as a colourless liquid.

EXAMPLE II.1

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)furan (Compound II.1).

Butyllithium (6.5 cm³, 2.5M in ether) was added dropwise with stirringto a solution of furan (1 g) in diethyl ether (40 cm³). After 90minutes, the reaction mixture was heated to reflux for 30 minutes andthen cooled to the ambient temperature. Powdered sulfur (0.48 g) wasadded portionwise with stirring. After 2 hours,4-bromo-1,1-difluorobut-1-ene (3.0 g) was added and stirring continuedat the ambient temperature for 18 hours. The reaction was quenched withwater and the product extracted into diethyl ether. The combined organicextracts were dried, filtered and evaporated to give a dark brownliquid. Chromatography on silica (eluant hexane-diethyl ether mixture)afforded Compound II.1 (0.965 g). ¹ H, NMR: δ 2.2-2.3(2H,m);2.7-2.8(2H,t); 4.15-4.35(1H,m); 6.4(1H,dd); 6.53(1H,d); 7.5(1H,d);(oil).

EXAMPLE II.2

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-5-methylfuran (Compound II.4).

Butyllithium (5.4 cm³, 2.5M in ether) was added dropwise with stirringto a solution of furan (1 g) in diethyl ether (40 cm³). After 90minutes, the reaction mixture was heated under reflux for 30 minutes andthen cooled to the ambient temperature. Powdered sulfur (0.38 g) wasadded portionwise with stirring. After 2 hours,4-bromo-1,1-difluorobut-1-ene (2.05 g) was added and stirring continuedfor 18 hours. The reaction was quenched with water and the productextracted into diethyl ether. The combined organic extracts were dried,filtered and evaporated. Chromatography on silica (eluant hexane-ethermixtures) afforded Compound II.4 (1.25 g). ¹ H NMR: δ 2.2-2.3(2H,m);2.3(3H,s); 2.7-2.77(2H,t); 4.16-4.34(1H,m); 5.97(1H,m); 6.43(1H,d);(oil).

EXAMPLE II.3

This Example illustrates a preparation of3-(4,4-difluorobut-3-enylthio)-2-methylfuran (Compound II.7).

A solution containing 2-methyl-3-furanthiol (2.0 g),4-bromo-1,1-difluorobut-1-ene (3.24 g) and potassium carbonate (2.48 g)in acetone (50 cm³) was heated under reflux for 2 hours and then left tostand for 18 hours. The reaction was quenched with water and the productextracted into diethyl ether. The combined organic extracts were dried,filtered and evaporated. Chromatography on silica (eluant 10% ether inhexane) afforded Compound II.7 (2.338 g); M⁺ =204; ¹ H NMR: δ2.1-2.25(2H,m); 2.35(3H,s); 2.65(2H,t); 4.1-4.3(1H,m); 6.3(1H,d);7.3(1H, d); (oil).

EXAMPLE II.4

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylsulfinyl)furan (Compound II.2).

3-Chloroperbenzoic acid (0.54 g of a 50% by weight solid, 1.58 mM) wasadded portionwise to a solution of Compound II.1 (0.30 g) indichloromethane (5 cm³) with ice-bath cooling. After stirring for 4hours, the reaction was partitioned between ethyl acetate and 2M NaOHsolution. The organic layer was separated, washed with more 2M NaOHsolution, dried over magnesium sulfate, filtered and evaporated to giveCompound II.2 (0.210 g). ¹ H NMR: δ 2.3-2.5(2H,m); 3.1-3.4(2H,m);4.15-4.35(1H,m); 6.5(1H,dd); 7.0(1H,d); 7.7(1H,d); (oil).

The following compounds according to the invention were prepared by theabove procedure:

(i) 2-(4,4-difluorobut-3-enylsulfonyl)furan (Compound II.3); ¹ H NMR: δ2.4-2.55(2H,m); 3.25-3.3(2H,t); 4.1-4.3 (1H,m); 6.6(1H,dd); 7.23(1H,d);7.67(1H,d) (oil) from Compound II.1 using 2.1 equivalents of oxidant.

(ii) 2-(4,4-difluorobut-3-enylsulfinyl)-5-methylfuran (Compound II.5); ¹H NMR: δ 2.3-2.45(5H,m); 3.0-3.15 and 3.3-3.4(total 2H,m);4.2-4.3(1H,m); 6.1(1H,d); 6.85(1H,d); (oil) from Compound II.4 using 1equivalent of oxidant.

(iii) 2-(4,4 difluorobut-3-enylsulfonyl)5-methylfuran (Compound II.6); ¹H NMR: δ 2.4-2.55(5H,m); 3.2-3.28 (2H,t); 4.15-4.3(1H,m); 6.2(1H,d);7.1(1H,d); (oil) from Compound II.4 using 2.1 equivalents of oxidant.

(iv) 3-(4,4-difluorobut-3-enylsulfinyl)-2-methylfuran (Compound II.8); ¹H NMR: δ 2.3-2.45(5H,m); 2.8-2.9 and 3.1-3.2(total 2H, m);4.2-4.35(1H,m); 6.66(1H,d); 7.4(1H,d) from Compound II.4 using 1equivalent of oxidant.

(v) 3-(4,4-difluorobut-3-enylsulfonyl)-2-methylfuran (Compound II.9); ¹H NMR: 2.42-2.52(2H,m); 2.6(3H,s); 3.2-3.28(2H,t); 4.1-4.23(1H,m);6.6(1H,d); 7.36(1H,d) from Compound II.4 using 2.1 equivalents ofoxidant.

EXAMPLE III.1

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)thiophene (Compound III.1).

A solution containing 2-mercaptothiophene (10 g),4-bromo-1,1-difluorobut-1-ene (15.47 g) and potassium carbonate (11.87g) in acetone (250 cm³) was heated under reflux for 2 hours and thenleft to stand for 18 hours. The reaction was quenched with water andextracted several times with diethyl ether. The combined organicextracts were dried over magnesium sulfate, filtered and evaporated togive an amber oil. Chromatography on silica (eluant 5% ether in hexane)afforded Compound III.1 (9.5 g); M⁺ =206; ¹ H NMR: δ 2.2-2.4(2H,m);2.8(2H,t); 4.1-4.3(1H,m); 6.95-7.0(1H,dd); 7.15(1H,d); 7.35(1H,d);(oil).

The following compound according to the invention was prepared by theabove procedure.

(i) 2-(4,4-difluorobut-3-enylthio)beno b!thiophene (Compound III.10); ¹H NMR: δ 2.2-2.3(2H,m); 2.7-2.8(2H,t); 4.15-4.35(1H,m); 6.4(1H,dd);6.53(1H,d); 7.5(1H,d) from benzthiophene.

EXAMPLE III.2

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-5-formylthiophene (Compound III.4).

Compound III.1 (1.0 g) was added slowly to a solution containingdimethyl formamide (0.48 cm³) and phosphoryl chloride (0.56 cm³). Thereaction mixture was heated at 100° C. for 2 hours, cooled in anice-bath and then neutralised with 2M NaOH solution. The aqueoussolution was extracted twice with diethyl ether and the combined organiclayers were washed with water and NaHCO₃ solution. The organic extractswere dried over magnesium sulfate, filtered and evaporated to give adark liquid. Filtration through silica (eluant 20% diethyl ether inhexane) afforded Compound III.4 (0.91 g). M⁺ =234; ¹ H NMR: δ 2.4(2H,m);3.0(2H,t); 4.2-4.4(1H,m); 7.1(1H,d); 7.7(1H,d); 9.8(1H,s); (oil).

EXAMPLE III.3

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-5-hydroxymethylthiophene (CompoundIII.5).

Sodium borohydride (0.065 g) was added to a solution of Compound III.4(0.75 g) in ethanol (21 cm³) and water (9 cm³). The reaction mixture wasstirred at the ambient temperature for 2 hours, quenched with 2Mhydrochloric acid and then partitioned between water and diethyl ether.The organic phase was dried over magnesium sulfate, filtered andevaporated to give a greenish liquid. Chromatography on silica (eluant20% ethyl acetate in hexane) afforded Compound III.5 (0.44 g). M⁺ =236;¹ H NMR: δ 1.8-2.0(1H,br s); 2.3(2H,m); 2.8(2H,t); 4.1-4.3(1H,m);4.8(2H,s); 6.8(1H,d); 7.0(1H,d); (oil).

EXAMPLE III.4

This Example illustrates a preparation of (E)- and(Z)-2-(4,4-difluorobut-3-enylthio)-5-hydroximinothiophene (CompoundsIII.6 and III.7).

Hydroxylamine hydrochloride (0.9 g) and sodium hydrogen carbonate (1.09g) were stirred together in ethanol (15 cm³) and water (15cm³) for 5minutes. Compound III.4 (3 g) was added and the reaction mixture wasstirred at the ambient temperature for 2 hours and then left to standfor 18 hours. The reaction mixture was partitioned between water anddiethyl ether. The organic phase was dried over magnesium sulfate,filtered and evaporated to give an amber liquid (3.4 g). Chromatographyon silica (eluant 20% ethyl acetate in hexane)afforded Compounds III.6(1.5 g) and III..7 (1.3 g). M⁺ =249; ¹ H NMR: δ 2.25-2.35(2H,m);2.85(2H,t); 4.14-4.35(1H,m); 7.05(2H,m); 7.52(1H,br s); 8.18(1H,s);(oil) and M⁺ =249; δ 2.25-2.38(2H,m); 2.85-2.95(2H,t); 4.18-4.35(1H,m);7.08(1H,d); 7.25(1H,d); 7.64(1H,s); (oil).

EXAMPLE III.5

This Example illustrates a preparation of5-cyano-2-(4,4-difluorobut-3-enylthio)-thiophene (Compound III.8).

1,1'-carbonyl-diimidazole (0.326 g) was added to a solution of CompoundIII.6 (0.5 g) and the reaction mixture was stirred at the ambienttemperature for 10 minutes, then heated under reflux for 2 hours andleft to stand for 18 hours. A further equivalent of1,1'-carbonyl-diimidazole was added and the reaction mixture heatedunder reflux for 1 hour. The reaction mixture was filtered throughcelite and then evaporated to give Compound III.8 (0.28 g). ¹ H NMR: δ2.27-2.38(2H,m); 2.94(2H,t); 4.15-4.33(1H,m); 7.05(1H,d); 7.5(1H,d);(oil).

EXAMPLE III.6

This Example illustrates a preparation of5-acetyl-2-(4,4-difluorobut-3-enylthio)thiophene (Compound III.9).

A solution of methylmagnesium bromide (1.3 cm³, 3M solution in diethylether, 3 equiv.) was added slowly to a solution of Compound III.8 (0.3g) in tetrahydrofuran (10 cm³). The reaction mixture was stirred at theambient temperature for 3 hours and then the solvent was evaporated. Theresidue was partitioned between ammonium hydroxide solution andchloroform. The organic layer was washed with water, dried over Na₂ SO₄and evaporated. The residue was chromatographed on silica (eluant 10%ethyl acetate in hexane) to give Compound III.9 (0.16 g). ¹ H NMR: δ2.30-2.40(2H,m); 2.50(3H,s); 2.97(2H,t); 4.15-4.33(1H,m); 7.04(1H,d);7.55(1H,d); (oil).

EXAMPLE III.7

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylsulfinyl)thiophene (Compound III.2).

Compound III.1 (0.50 g) was stirred at ambient temperature indichloromethane (5 cm³) and 3-chloro perbenzoic acid (0.834 g of a 50%by weight solid, 1 equiv.) was added. After tlc indicated consumption ofstarting material the reaction was quenched by the addition of asaturated aqueous solution of sodium bicarbonate and the product wasextracted into dichloromethane. The organic phase was separated, washedwith saturated brine and dried over magnesium sulfate. After filtrationand concentration by evaporation under reduced pressure, there wasobtained a liquid (0.584 g) which was purified by chromatography onsilica gel using 20% ethyl acetate in hexane as eluant, and then diethylether to elute Compound III.2 (0.29 g). ¹ H NMR: δ 2.3-2.55 (2H,m);2.9-3.2 (2H, m); 4.2-4.5 (1H, m); 7.15 (1H, m); 7.5 (1H, m); 7.7 (1H,m); (oil).

The following compounds according to the invention were prepared by theabove procedure:

(i) 2-(4,4-difluorobut-3-enylsulfonyl)thiophene (Compound III.3). ¹ HNMR: δ 2.4-2.6(2H,m); 3.2-3.4(2H,t); 4.1-4.3 (1H, m); 7.15(1H,dd);7.7-7.8(1H,m); (oil) from Compound III.1 using two equivalents ofoxidant.

(ii) 2-(4,4-difluorobut-3-enylsulfinyl)benzo b!thiophene (CompoundIII.11). ¹ H NMR: δ 2.3-2.4(2H,m); 3.0-3.2(2H,m); 4.2-4.4(1H,m);7.45(2H,m); 7.9(2H,m); 7.75(1H,s) from Compound III.10 using oneequivalent of oxidant.

(iii) 2-(4,4-difluorobut-3-enylsulfonyl)benzo b!thiophene (CompoundIII.12). ¹ H NMR: δ 2.5(2H,m); 3.3(2H,t); 4.2-4.35(1H,m); 7.5(2H,m);7.9(3H,m) from Compound III.10 using two equivalents of oxidant.

EXAMPLE IV.1

This Example illustrates a preparation of ethyl5-(4,4-difluorobut-3-enylthio)-3-methylisoxazole-4-carboxylate (CompoundIV.8).

A solution of 4,4-difluorobut-3-enyl thioacetate (2 g) in 50% sodiumhydroxide solution (6.7 cm³) was stirred vigorously for 30 minutes. Asolution of ethyl 5-chloro-4-methylisoxazole (2.2 g) in dichloromethane(12 cm³) was added followed by tetra-n-butylammonium bromide (catalyst)and the reaction stirred at the ambient temperature under nitrogen.After 3 hours the layers were separated and the organic phase was washedwith brine, dried (MgSO₄), filtered and evaporated under reducedpressure. The residue was stirred with 880 ammonia resulting incrystallisation. The crystals were isolated by filtration to giveCompound IV.8 (2.87 g). ¹ H NMR δ 1.35(3H,t); 2.45(3H,s); 2.50(2H,m);3.20(2H,t); 4.25(1H,m); 4.30(2H,q); (mp 41-42° C.).

EXAMPLE IV.2

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylthio)-3-methylisoxazole-4-carboxylic acid(Compound IV.9).

A solution of Compound IV.8 (0.5 g) in isopropanol (5 cm³) and 2M NaOH(1 cm³) was stirred for 3 hours. The mixture was then poured into waterand washed with ethyl acetate. The aqueous layer was then acidified with2M HCl and the product extracted into ethyl acetate. This extract wasdried (MgSO₄), filtered and evaporated under reduced pressure to giveCompound IV.9 (0.16 g). M⁺ =249; ¹ H NMR δ 2.45(3H,s); 2.50(2H,m);3.20(2H,t); 4.20-4.40(1H,m); (mp 132-133° C.).

EXAMPLE IV.3

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylthio)-3-methylisoxazole-4-oxamide (CompoundIV.7).

Triethylamine (0.33 cm³) and ethyl chloroformate (0.24 cm³) were addedto Compound IV.9 (0.56 g) in dichloromethane (15 cm³) at 0° C. Thereaction was allowed to warm to the ambient temperature and stirred for2 hours. Ammonia was bubbled through the solution until it was saturatedand the reaction was then stirred for a further 1 hour. Aqueous ammoniawas added and the product extracted into dichloromethane. The organicphase was washed with water, dried (MgSO₄), filtered and evaporatedunder reduced pressure. Purification by distillation in a kugelrohrapparatus gave Compound IV.7 (0.069 g). ¹ H NMR δ 2.45(2H,m);2.50(3H,s); 3.25(2H,t); 4.25(1H,m); (mp 87° C.).

EXAMPLE IV.4

This Example illustrates a preparation of3-(5-chlorofur-2-yl)-5-(4,4-difluorobut-3-enylthio)isoxazole (CompoundIV.23).

Hydrogen sulfide was bubbled through a stirred solution of potassiummethoxide (1.9 g) in ethanol (10 cm³) cooled in an acetone/ice bath.5-Chloro-3-(5-chlorofur-2-yl)isoxazole (2.2 g) was added and thereaction was then heated under reflux for 1 hour during which time thesolvent evaporated. Acetone (10 cm³) and 4-bromo-1,1-difluorobut-1-ene(2 g) were added and the mixture heated under reflux for a further 2hours. The resulting solution was cooled, poured into diethyl ether andbrine and the layers separated. The aqueous layer was extracted withether. The combined organic phases were washed with brine, dried(MgSO₄), filtered and evaporated under reduced pressure to give a blacksolid. Purification by column chromatography on silica gel using 10%ether in hexane as eluant gave Compound IV.23 (2 g). M⁺ =291; ¹ H NMR δ2.35-2.50(2H,m); 3.10(2H,t); 4.30(1H,m); 6.30(1H,d); 6.43(1H,s);6.90(1H,d); (mp 80-82° C.).

The following compound according to the invention was prepared by theabove procedure:

(i) 5-(4,4-difluorobut-3-enylthio)-3-phenylisoxazole (Compound IV.1). M⁺=267; ¹ H NMR: δ 2.43(2H,m); 3.10(2H,t); 4.28(1H,m); 6.50(1H,s);7.45(3H,m); 7.78(2H,m); (oil) from 5-chloro-3-phenylisoxazole.

EXAMPLE IV.5

This Example illustrates a preparation of5(4,4-difluorobut-3-enylthio)-3-methylisoxazole (Compound IV.10).

To a stirred solution of acetone oxime (0.365 g) in dry tetrahydrofuran(20 cm³) at 0° C. under nitrogen was added n-butyl lithium (4.6 cm³ of a2.5M solution in hexanes) resulting in formation of a pale yellowprecipitate. After stirring at 0° C. for 30 minutes, carbon disulfide(0.3 cm³) was added producing a bright orange solution. After a further10 minutes, 3M HCl (20 cm³) was added and the reaction was heated underreflux for 3 hours and then cooled. The layers were separated and theaqueous layer was extracted with chloroform. The combined organic layerswere dried (MgSO₄), filtered and evaporated under reduced pressure togive a brown oil. The oil was then taken up in acetone (11 cm³) and1-bromo-4,4-difluorobut-3-ene (0.77 g) and potassium carbonate (0.87 g)were added and the reaction heated under reflux for 3.5 hours and thencooled. The mixture was then poured into ethyl acetate and 2M HCl andthe layers separated. The aqueous layer was extracted with ethyl acetateand the combined organic phases were dried (MgSO₄), filtered andevaporated under reduced pressure to give a brown oil. Purification bycolumn chromatography on silica gel using 1:9 ethyl acetate : hexane aseluant gave 2-(4,4-difluorobut-3-enylthio)-3-methylisoxazole (0.105 g).M⁺ =205; ¹ H NMR: δ 2.30(3H,s); 2.40(2H,m); 3.05(2H,t); 4.25(1H,m);6.00(1H,s); (oil).

EXAMPLE IV.6

This Example illustrates a preparation of3-(5-chlorofur-2-yl)-5-(4,4-fluorobut-3-enylsulfonyl)isoxazole (CompoundIV.24).

To a stirred solution of Compound IV.23 (2 g) in methanol (40 cm³),cooled in an ice/acetone bath was added magnesium monoperoxyphthalate(9.4 g). After stirring for 30 minutes the cooling bath was removed andthe reaction allowed to warm to the ambient temperature and stirred for1 hour. The mixture was poured into diethyl ether and brine and thelayers separated. The combined organic phases were washed with 2M NaOH,water and brine, dried (MgSO4), filtered and evaporated under reducedpressure to give Compound IV.24 (1.9 g). M⁺ =323; ¹ H NMR: δ2.50-2.60(2H,m); 3.40(2H,t); 4.25(1H,m); 6.38(1H,d); 7.05(1H,d);7.20(1H,s); (mp 86.5-88.5° C.).

The following compounds according to the invention were prepared by theabove oxidation procedure:

(i) 5-(4,4-difluorobut-3-enylsulfinyl)-3-phenylisoxazole (CompoundIV.2). M⁺ =283; ¹ H NMR: δ 2.53(2H,m); 3.25(2H,t); 4.29(1H,m);7.18(1H,s); 7.50(3H,m); 7.80(2H,m); (oil) from Compound IV.1 and oneequivalent of oxidant.

(ii) 5-(4,4-difluorobut-3-enylsulfonyl)-3-phenylisoxazole (CompoundIV.3). M⁺ =299; ¹ H NMR: δ 2.57(2H,m); 3.43(2H,t); 4.27(1H,m);7.2(1H,s); 7.51(3H,m); 7.80(2H,m); (mp 57-58.5° C.) from Compound IV.1and two equivalents of oxidant.

(iii) 3-(thien-2-yl)-5-(4,4-difluorobut-3-enylsulfonyl)isoxazole(Compound IV.26). M⁺ =305; ¹ H NMR: δ 2.50-2.63(2H,m); 3.41(2H,t);4.27(1H,m); 7.20(1H,s); 7.14-7.23(1H,m); 7.52(2H,m); (mp 55-57° C.) from3-(thien-2-yl)-5-(4,4-difluorobut-3-enylthio)isoxazole, Compound IV.25,itself prepared from 5-chloro-3-(thien-2-yl)isoxazole by the procedureof Example IV.4.

EXAMPLE V.1

The Example illustrates a preparation of3-chloro-4-cyano-5-(4,4-difluorobut-3-enylthio)isothiazole (CompoundV.2).

A solution of 4-cyano-3,5-dichloroisothiazole (1 g) in methanol (10 cm³)was added over 15 min to a solution of sodium sulfide nonahydrate (1.3g) in water (2.6 cm³) and methanol (25 cm³) heated at 50° C. Thereaction was stirred for 1 hour and then the solvent was evaporatedunder reduced pressure to give a yellow solid. This residue wasdissolved in acetone (20 cm³), 4-bromo-1,1-difluorobut-1-ene (0.68 g)was added and the reaction was stirred for 12 hours. The resultingmixture was poured into water and the layers separated. The aqueouslayer was extracted with ethyl acetate. The combined organic phases weredried (MgSO₄), filtered and evaporated under reduced pressure.Purification by column chromatography on silica gel using 1:1 ethylacetate:hexane as eluant gave Compound V.2, (0.88 g). M⁺ =266; ¹ H NMR δ2.50(2H,m); 3.20(2H,t); 4.20-4.40(1H,m); (oil).

The following compound according to the invention was prepared by theabove procedure but using 2 equivalents of sodium sulfide nonahydrateand 4-bromo-1,1-difluorobut-1-ene:

(i) 3,5-bis-(4,4-difluorobut-3-enylthio)cyanoisothiazole (CompoundV.12). ¹ H NMR δ 2.40-2.60(4H,m); 3.20(2H,t); 3.30(2H,t);4.20-4.40(2H,m); (oil).

EXAMPLE V.2

The Example illustrates a preparation of5-(4,4-difluorobut-3-enylsulfonyl)-4-cyanoisothiazole (Compound V.6) and3,5-bis-(4,4-difluorobut-3-enylsulfonyl)-4-cyanoisothiazole (CompoundV.15).

To a solution of Compound V.12 (0.1 g) in dichloromethane (5 cm³) wasadded 3-chloroperbenzoic acid (0.42 g) and the reaction mixture wasstirred until starting material had disappeared. The reaction mixturewas poured into ethyl acetate and water and the layers were separated.The aqueous layer was extracted with ethyl acetate. The combined ethylacetate phases were washed with sodium hydrogen carbonate, dried(MgSO₄), filtered and evaporated under reduced pressure. The residue wastaken up in diethyl ether and triethylamine was added causing thesolution to become cloudy. The ether solution was then washed withwater, dried (NgSO₄), filtered and evaporated. Purification of theresidue by column chromatography on silica gel using 1:1 ethylacetate:hexane as eluant gave Compound V.15 (0.01 g); M⁺ =418; ¹ H NMR δ2.60-2.70(4H,m); 3.60(4H,t); 4.30(2H,m); (oil) and Compound V.6 (0.08g); M⁺ =264; ¹ H NMR δ 2.60(2H,m); 3.60(2H,t); 4.30(1H,m); 9.40(1H,s);(oil).

EXAMPLE VI.1

Oxazoles substituted with a 4,4-difluorobut-3-enylthio group in the 2, 4or 5-position may be prepared starting from a correspondinglysubstituted mercapto-oxazole and an appropriate difluorobut-1-enealkylating agent. This is illustrated by the following preparation of2-(4,4-difluorobut-3-enylthio)-5-phenyloxazole (Compound VI.18).

To a solution of 2-mercapto-5-phenyloxazole (0.44 g) in acetone (15 cm³)was added 4,4-difluoro-3-butenyl 4-methyl-benzenesulfonate (0.7 g) andpotassium carbonate (0.369 g) and the reaction was heated at reflux fora total of 8 hours after which time some of the starting tosylateremained. Further 2-mercapto-5-phenyloxazole (0.05 g) was added and theheating continued for 5 hours. The reaction mire was cooled, poured intodiethyl ether and water and the layers separated. The aqueous layer wasextracted with ether and the combined organic phases were dried (MgSO₄)and evaporated under reduced pressure to give a yellow liquid.Chromatography on silica gel using 5% tert-butyl dimethyl ether inhexane gave Compound VI.18; M⁺ =267; ¹ H NMR (CDCl₃) δ 2.51(2H,m);3.23(2H,t); 4.30(1H,m); 7.23-7.47(4H,m); 7.58(2H,d); (oil).

The following compounds according to the invention were prepared by theabove procedure:

(i) 2-(4,4-difluorobut-3-enylthio)-oxazole (Compound VI.1). ¹ H NMR(CDCl₃) δ 2.45(2H,m); 3.20(2H,t); 4.25(1H,m); 7.10(1H,s); 7.66(1H,s);(oil) from oxazole-2-thione.

(ii) 2-(4,4-difluorobut-3-enylthio)-4-methyloxazole (Compound VI.6). M⁺205; ¹ H NMR δ: 2.04(3H,s); 2.45(2H,m); 3.18(2H,t); 4.25(1H,m);7.38(1H,q); (oil) from 2-mercapto-4-methyloxazole.

EXAMPLE VI.2

This Example illustrates a 3-step preparation of methyl2-(4,4-difluorobut-3-enylthio)-4-methyloxazole-5-carboxylate (CompoundVI.32).

Step 1: Methyl 2-amino-4-methyloxazole-5-carboxylate.

Methyl 3-chloroacetoacetate (75 g) and urea (90 g) in methanol (200 cm³)were stirred and heated to reflux for 24 hours. The reaction mixture wascooled to ambient temperature and the precipitate filtered fromsolution, washed with cold methanol and sucked to dryness. This solidwas treated with aqueous 2M sodium hydroxide and the product extractedinto ethyl acetate (several portions). Evaporation of solvent underreduced pressure gave a colourless solid (14.5 g) which wasrecrystallised from acetonitrile, mp 225° C. (dec.) ¹ H NMR (DMSO-d₆): δ2.15(3H,s); 3.75(3H,s); 7.4(2H,br).

Step 2: Methyl 2-chloro-4-methyloxazole-5-carboxylate.

The product from Step 1 (1.56 g) was partially dissolved in dryacetonitrile (40 cm³) and added in portions at 8° C. to a stirredmixture of copper (II) chloride (1.61 g) and tertiary butyl nitrite inacetonitrile (dry, 20 cm³) under an atmosphere of nitrogen. Theresulting brown solution was stirred at 20° C. for 2 hours andevaporated under reduced pressure. The residue was treated with aqueous2M hydrochloric acid, and the product extracted into diethyl ether. Theorganic phase was dried (MgSO₄) and then washed through a short columnof silica gel with more ether. The filtrate was evaporated under reducedpressure to give the required intermediate (0.9 g) as a yellow solid M⁺=175.

Step 3: Methyl 2-(4,4-difluorobut-3-enylthio)methyloxazole-5-carboxylate

The product from Step 2 (0.176 g) and thiourea (0.084 g) were stirred inethanol (5 cm³) and heated to reflux under an atmosphere of nitrogen for5 hours. The reaction was cooled and solvent removed by evaporationunder reduced pressure to give a yellow gum which was dissolved inacetone containing 4-bromo-1,1-difluorobut-1-ene (0.17 g) and potassiumcarbonate (0.2 g). This mixture was stirred for 1 hour under anatmosphere of nitrogen at ambient temperature and stored for 18 hours.The solvent was evaporated under reduced pressure and the residuetreated with water and diethyl ether. The organic phase was separated,dried (MgSO₄) and evaporated to give Compound VI.32 (0.095 g); M⁺ =175.¹ H NMR: δ 2.45(5H,m); 3.22 (2H,t); 3.90(3H,s); 4.25(1H,m); (oil).

EXAMPLE VI.3

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-4-methyloxazole-5-carboxylic acid(Compound VI.37).

Compound VI.32 (0.4 g) was dissolved in propan-2-ol (10 cm³) containingaqueous sodium hydroxide (2 cm³ of 2M solution) and stirred for 5 hoursat ambient temperature. The mixture was evaporated under reducedpressure and the residue diluted with water, extracted with ethylacetate, acidified with dilute hydrochloric acid and re-extracted withethyl acetate (3×100 cm³). The latter extracts were combined, washedwith saturated brine, dried (MgSO₄) and evaporated under reducedpressure to give the required product as a colourless solid (0.3g). M⁺=249; ¹ H NMR: δ 2.5(5H,m); 3.27(2H,t); 4.27(1H,m); 6.5(1H,br s); (mp66-68° C.). The sodium salt of this compound was prepared by treating asample (0.7 g) with a solution of sodium methoxide in dry methanol(0.061 g of sodium metal dissolved in methanol (10 cm³)) at ambienttemperature. Evaporation of solvent under reduced pressure gave thesodium salt of Compound VI.37 as a colourless solid; M⁺ (FAB)=271; (mp211-212° C.).

The following compound according to the invention was prepared by theabove procedure:

(i) 2-(4,4-difluorobut-3-enylthio)-4-trifluoromethyloxazole-5-carboxylicacid (Compound VI.36). M⁺ =303; ¹ H NMR: δ 2.54(2H,m); 3.32(2H,t);4.28(1H,m) 7.65(1H,br s) from Compound VI.31.

EXAMPLE VI.4

This example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-4-trifluoromethyloxazole (Compound VI.4).

2-Amino-4-trifluoromethyloxazole (0.84 g) in dichloromethane (25 cm³)containing bis-(4,4-difluorobut-3-enyl)disulfide (2.71 g) at 0° C. wasstirred and treated dropwise with tert. butyl nitrite (0.62 g) undernitrogen. The reaction solution was evaporated under reduced pressureand the residue fractionated by chromatography (silica, eluant hexane)to give Compound VI.4 (0.35 g). M⁺ =259; ¹ H NMR: δ 2.50(2H,m);3.26(3H,t); 4.28(1H,m); 7.95(1H,q); (oil).

The following compound according to the invention was prepared by theabove procedure from the corresponding aminooxazole:

(i) Ethyl2-(4,4-difluorobut-3-enylthio)-4-trifluoromethyloxazole-5-carboxylate(Compound VI.31). MH⁺ =322; ¹ H NMR: δ 1.40(3H,t); 2.52(2H,m);3.30(2H,m); 4.28(1H,m); 4.43(2H,q); (oil) from ethyl2-amino-4-trifluoromethyloxazole-5-carboxylate (prepared from ethyl1,1,1-trifluoromethylacetoacetate and urea in a procedure analogous toExample VI.2).

EXAMPLE VI.5

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-5-chlorooxazole (Compound VI.13).

Compound VI.1 (2.0 g) was dissolved in acetonitrile (50 cm³) containingN-chlorosuccinimide (1.50 g) and stirred at ambient temperature for 24hours. The mixture was evaporated under reduced pressure, extracted withhexane (50 cm³), filtered and the filtrate evaporated under reducedpressure. The residue was fractionated by chromatography (silica; eluant20% diethyl ether in hexane) to give Compound VI.13 (0.75 g). M⁺ =225; ¹H NMR: δ 2.46(2H,m); 3.16(2H,t); 4.28(1H,m); 6.86(1H,s); (oil).

The following compound according to the invention was prepared fromCompound VI.6 by the above procedure:

(i) 2-(4,4-difluorobut-3-enylthio)4-methyl-5-chlorooxazole (CompoundVI.15). M⁺ =239; ¹ H NMR: δ 2.05(3H,s); 2.45(2H,m); 3.15(2H,t);4.25(1H,m); (oil).

EXAMPLE VI.6

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-4-methyloxazole-5-carboxamide (CompoundVI.40).

Compound VI.32 (1.5 g) was dissolved in methanol (10 cm³) and treatedwith aqueous ammonia (35 cm³, density 0.88) at ambient temperature. Themixture was stirred for 5 hours, diluted with brine and the productextracted into ethyl acetate (2×100 cm³). The combined organic phaseswere washed with brine (4×50 cm³), dried (MgSO₄) and evaporated underreduced pressure; the residue was washed with hexane to give CompoundVI.40 (1 g). M⁺ =248; ¹ H NMR (DMSO-d₆): δ 2.50(5H,m); 3.26(2H,t);3.85(3H,s); 4.28(1H,m); 5.6, 6.0 (2H,br s); (mp 72-73° C.).

EXAMPLE VI.7

This Example illustrates a preparation of5-cyano-2-(4,4-difluorobut-3-enylthio)-4-methyloxazole (Compound VI.25).

Compound VI.40 (0.64 g) was dissolved in dichloromethane (10 cm³)containing dry pyridine (1cm³) at ambient temperature and treated withmethane sulfonyl chloride (0.5 cm³). The solution was stirred for 5hours, stored for 72 hours, further methane sulfonyl chloride (0.25 cm³)and pyridine (0.5 cm³) added, stirred for 8 hours, and stored for 48hours. The mixture was treated with dilute hydrochloric acid, and theproduct exalted into ethyl acetate. The combined organic phase waswashed with brine and dried (MgSO₄). After filtration, the solvent wasevaporated under reduced pressure and the residue fractionated bychromatography (silica; eluant 10% ethyl acetate in hexane) to giveCompound VI.25 (0.46 g). M⁺ =230; ¹ H NMR: δ 2.32(3H,s); 2.50(2H,m);2.58(3H,s); 3.25(2H,t); 3.85(3H,s); 4.28(1H,m); (oil).

EXAMPLE VI.8

This Example illustrates a preparation of N-methylsulfonyl2-(4,4-difluorobut-3-enylthio)-4-methyl-oxazolecarboxamide (CompoundVI.38).

The sodium salt of Compound VI.37 (0.52 g) was stirred in hexane (6.5cm³) and treated with oxalyl chloride (0.275 g) at ambient temperature.The mixture was stirred for 6 hours, stored for 18 hours and evaporatedunder reduced pressure. The residue, containing the oxazole carbonylchloride derivative, was treated with a solution of methane sulfonamide(0.20 g) in dry butan-2-one (5 cm³), heated under reflux with stirringfor 8 hours, cooled to ambient temperature and stored for 18 hours. Themixture was evaporated under reduced pressure, the residue dissolved inwater, acidified with 2M hydrochloric acid and the product extractedinto diethyl ether (2×150 cm³). The ether extracts were combined, washedwith aqueous saturated sodium chloride, dried (MgSO₄), evaporated underreduced pressure and the residue purified by chromatography, (silica;eluant acetonitrile), to give Compound VI.38 (0.20 g). M⁺ =326; ¹ H NMR:δ 2.50(5H,m); 3.27(2H,t); 3.40(3H,s); 4.28(1H,m); (mp 60-62° C.).

EXAMPLE VI.9

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylsulfinyl)-5-phenyloxazole (Compound VI.19).

To a solution of Compound VI.18 (1 g) in dichloromethane (40 cm³) wasadded 3-chloroperbenzoic acid (1.3 g of a 50% by weight solid, (1 eq))and the reaction was stirred at ambient temperature for 5 hours. Thereaction mixture was poured into a mixture of diethyl ether and aqueoussodium bicarbonate and the layers separated. The organic layer was dried(MgSO₄) and evaporated under reduced pressure to give a white solidwhich was purified by chromatography on silica gel, eluting with 1:4ethyl acetate:hexane to give Compound VI.19 (0.567 g). M⁺ =283; ¹ H NMR:δ 2.50(2H,m); 3.41(2H,t); 4.29(1H,m); 7.27(1H,s); 7.38-7.55(3H,m);7.71(2H,d); (oil).

The following compounds were prepared from the corresponding thioethersby the general method described above but using 2 equivalents of3-chloroperbenzoic acid:

(i) 2-(4,4-difluorobut-3-enylsulfonyl)-4-trifluoromethyloxazole(Compound VI.5). ¹ H, NMR: δ 2.65(2H,m); 3.58(2H,t); 4.28(1H,m);8.24(1H,q); (oil).

(ii) 5-chloro-2-(4,4-difluorobut-3-enylsulfonyl)oxazole (CompoundVI.14). MNH₄ ⁺ =275; ¹ H NMR: δ 2.60(2H,m); 3.47(2H,t); 4.26(1H,m);7.18(1H,s); (oil).

(iii) 5Chloro-2-(4,4-difluorobut-3-enylsulfonyl)-4-methyloxazole(Compound VI.16). ¹ H, NMR: δ 2.25(3H,s); 2.60(2H,m); 3.45(2H,t);4.26(1H,m); (oil).

(iv) 2-(4,4-difluorobut-3-enylsulfonyl)-5-phenyloxazole (CompoundVI.20). M⁺ =299; ¹ H NMR: δ 2.62(2H,m); 3.51(2H,t); 4.27(1H,m);7.26(1H,s); 7.42-7.55(3H,m); 7.69-7.79(2H,d); (mp 55-59° C.).

EXAMPLE VII.1

This Example illustrates a general method for the preparation ofthiazoles substituted with a 4,4-difluorobut-3-enylthio group in the 2,4 or 5-position starting from a correspondingly substituted mercaptothiazole and an appropriate difluorobut-1-ene alkylating agent. This isdemonstrated by the following preparation of2-(4,4-difluorobut-3-enylthio)-5-phenylthiazole (Compound VII.17).

To a solution of 2-mercapto-5-phenylthiazole (0.483 g) in acetone (15cm³) was added 4,4difluoro-3-butenyl 4-methyl-benzenesulfonate (0.7 g)and potassium carbonate (0.369 g) and the reaction was heated at refluxfor a total of 8 hours after which time some of the starting tosylateremained. Further 2-mercapto-5-phenylthiazole (0.05 g) was added and theheating continued for 5 hours. The reaction mixture was cooled, pouredinto diethyl ether and water and the layers separated. The aqueous layerwas extracted with ether and the combined organic phases were dried(MgSO₄) and evaporated under reduced pressure to give a yellow liquid.Chromatography on silica gel using 5% tert-butyl dimethyl ether inhexane gave Compound VI.17 (0.582 g). M⁺ =283; ¹ H NMR: δ 2.51(2H,m);3.31(2H,t); 4.32(1H,m); 7.26(1H,s); 7.30-7.48(3H,m); 7.89(2H,d); (oil).

The following compounds according to the invention were prepared by theabove procedure:

(i) 2-(4,4-difluorobut-3-enylthio)-thiazole (Compound VII.1). M⁺ =207; ¹H NMR: δ 2.47(2H,m); 3.26(2H,t); 4.27(1H,m); 7.22(1H,d); 7.68(1H,d);(oil) from 2-mercaptothiazole.

(ii) 2-(4,4-difluorobut-3-enylthio)-thiazoline (Compound VII.134). M⁺=209; ¹ H NMR: δ 2.40(2H,m); 3.15(2H,t); 3.4(2H,t); 4.18-4.31(1H,m);4.2(2H,t); (oil) from 2-mercaptothiazoline.

EXAMPLE VII.2

This Example illustrates a two-step preparation of2-(4,4-difluorobut-3-enylthio)-4-trifluoromethyloxazole (CompoundVII.4).

Step 1: Preparation of 2-mercapto-4-trifluoromethylthiazole

1-Bromo-3,3,3-trifluoropropan-2-one (5.0 g) in tert. butanol (20 cm³)was treated with ammonium dithiocarbamate (2.9 g), the mixture stirredat ambient temperature for 18 hours, poured into water, extracted withethyl acetate and the organic phase dried (MgSO₄). The solvent wasevaporated under reduced pressure and the residue fractionated bychromatography (silica; eluant hexane:ethyl acetate 17:3 to 7:3 byvolume) to give a hydrate (2.16 g) of the required mercaptothiazole. Aportion (1.0 g) of this material was added to toluene (20 cm³)containing para toluene sulfonic acid (0.005 g, catalyst) and heatedunder reflux for 4 hours. The water formed during the reaction wasremoved using a Dean-Stark apparatus. The solution was cooled to ambienttemperature, washed with water, dried (MgSO₄) and evaporated underreduced pressure to give the required intermediate product (0.37 g); ¹ HNMR: δ 7.10(1H,s); 7.80(1H,s).

Step 2: Preparation of Compound VII.4

The product from Step 1 (0.37 g) in acetone (15 cm³) containinganhydrous potassium carbonate (0.3 g) and 4-bromo-1,1-difluorobut-1-ene(0.34 g) were stirred and heated under reflux for 4 hours. The mixturewas cooled, poured into water, extracted with ethyl acetate, dried(MgSO₄) and evaporated under reduced pressure to give Compound VII.4(0.30 g). M⁺ =275; ¹ H NMR: δ 2.50(2H,m);3.32(2H,t);4.28(1H,m);7.60(1H,s); (oil).

The following compounds according to the invention were prepared fromthe corresponding mercaptothiazoles using Step 2 of the above procedure:

(i) Ethyl 2-(4,4-difluorobut-3-enylthio)thiazole carboxylate (CompoundVII.8). ¹ H NMR: δ 1.40(3H,t); 2.48(2H,m); 3.32(2H,t); 4.28(1H,m);4.40(2H,q); 8.03(1H,s); from ethyl 2-mercaptothiazole-4-carboxylate.

(ii) Methyl2-(4,4-difluorobut-3-enylthio)-4-methylthiazole-5-carboxylate (CompoundVII.41). ¹ H NMR: δ 2.48(2H,m); 2.68(3H,s); 3.26(2H,t); 3.85(3H,s);4.28(1H,m); (oil) from methyl 2-mercapto-4-methylthiazole-5-carboxylate.

(iii) 2-(4,4-difluorobut-3-enylthio)-5-nitrothiazole (Compound VI.47).M⁺ =252; ¹ H NMR: δ 2.52(2H,m); 3.35(2H,m); 4.27(1H,m); 8.35(1H,s);(oil) from 2-mercapto-5-nitrothiazole (obtained from2-bromo-5-nitrothiazole and thiourea).

EXAMPLE VII.3

This Example illustrates a three-step preparation of5-chloro-2-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.24).

Step 1: 2-(bromo-3,4,4-trifluorobutylthio)thiazole

2-Mercaptothiazole (11.7 g) in acetone (30 cm³) containing1,4-dibromo-1,1,2-trifluorobutane (27.0 g) was treated portionwise withanhydrous potassium carbonate (13.8 g) under an atmosphere of nitrogen.The reaction was stirred for 1.5 hours, filtered and the insolubleswashed with further acetone (4×25 cm³). The filtrate was evaporatedunder reduced pressure and the residue fractionated by chromatography(silica, eluant 10% ethyl acetate in hexane) to give2-(4-bromo-3,4,4-trifluorobutylthio)thiazole (29.5 g). ¹ H NMR: δ22-2.5(2H,m); 3.2-3.6(2H,m); 4.7-5.0(1H,m); 7.23(1H,d); 7.68(1H,d).

Step 2: 2-(4-bromo-3,4,4-trifluorobutylthio)-5-chlorothiazole

The compound from Step 1 (30.6 g) in dichloromethane (130 cm³) wastreated at ambient temperature with sulfuryl chloride (9.6 cm³) indichloromethane (30 cm³) over 1 hour with stirring under an atmosphereof nitrogen. The reaction was stirred for a further 1 hour, pouredslowly into water (250 cm³) and stirred for 0.25 hours. The organicphase was separated, the aqueous phase extracted with dichloromethane(2×75 cm³), the combined organic phases washed with aqueous sodiumhydrogen carbonate, brine and dried (MgSO₄). The solvent was evaporatedunder reduced pressure and the residue fractionated by chromatography(silica; eluant 5% diethyl ether in hexane) to give2-(4-bromo-3,4,4-trifluorobutylthio)-5-chlorothiazole (28.0 g); ¹ H NMR:δ 2.20-2.45 (2H,m); 3.25-3.50(2H,m); 470-5.0(1H,m); 7.45(1H,s); (oil).

Step 3: Compound VII.24

Zinc powder (33 g) in water (600 cm³) was stirred with iodine (0.17 g,catalyst), heated to 80° C. and concentrated hydrochloric acid (0.5 cm³)added followed by the compound from Step 2 (125 g) in portions over 1.5hour under an atmosphere of nitrogen. Further zinc (16.6 g), iodine (0.1g) and hydrochloric acid (0.6 cm³) were added over 4 hours in portionsto complete the reaction. The mixture was cooled to ambient temperature,filtered through keiselghur using dichloromethane as solvent and thefiltrate extracted with dichloromethane (5×250 cm³). The combinedorganic phases were dried (MgSO₄), evaporated under reduced pressure andthe residue fractionated by chromatography on silica, eluting withhexane to give Compound VII.24 (140 g). M⁺ =241; ¹ H NMR: δ 2.42(2H,m);3.20(2H,t); 4.25(1H,m); 7.45(1H,s); (oil).

EXAMPLE VII.4

This Example illustrates a preparation of5-bromo-2-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.14).

2-Amino-5-bromothiazole hydrobromide (11 g) was treated with aqueoussodium hydrogen carbonate, extracted into dichloromethane (2×250 cm³)and dried (MgSO₄). The mixture was filtered and the filtrate added tobis-(4,4-difluorobut-3-enyl)disulfide (20 g). Tert. butyl nitrite (9.6cm³) in dichloromethane (40 cm³) was added dropwise to the stirredsolution at ambient temperature under an atmosphere of nitrogen. Thereaction was stirred for 18 hours, evaporated onto silica, the residueadded to a short column of silica which was eluted with (1) hexane and(2) hexane:diethyl ether, 20:1 by volume to give Compound VII.14 (6.4g). M⁺ =285; ¹ H NMR: δ 2.46(2H,m); 3.24(3H,t); 4.27(1H,m); 7.54(1H,s);(oil).

EXAMPLE VII.5

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-4-methylthiazole-5-sulfonyl fluoride(Compound VII.52) using an alternative diazotisation procedure to thatgiven in Example VII.4.

2-Amino-4-methylthiazole sulfonylfluoride (1.5 g) in acetonitrile (10cm³) was added dropwise to a stirred mixture of tert. butyl nitrite(1.65 cm³) and bis-(4,4-difluorobut-3-enyl)disulfide (2.25 g) inacetonitrile (50 cm³) at 60° C. under an atmosphere of nitrogen. Themixture was heated for 1 hour, evaporated under reduced pressure and theresidue fractionated by chromatography (silica; eluant hexane:ethylacetate 4:1 by volume) to give Compound VII.52 (1.84 g). M⁺ =303; ¹ HNMR: δ 2.50(2H,m); 2.68(3H,s); 3.32(2H,t); 4.28(1H,m); (oil).

The following compounds according to the invention were prepared fromthe corresponding aminothiazoles using the above procedure.

(i) 2-(4,4-difluorobut-3-enylthio)-5-methylthiazole (Compound VII.21).M⁺ =221; ¹ H NMR: δ 2.45(5H,m); 3.22(2H,t); 4.26(1H,m); 7.30(1H,s);(oil) from 2-amino-5-methylthiazole.

(ii) 5-chloro-2-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.24).M⁺ =241; ¹ H NMR: δ 2.45(2H,m); 3.22(2H,t); 4.26(1H,m); 7.45(1H,s);(oil) from 2-amino-5-chlorothiazole in an alternative method to that ofExample VII.3 above.

(iii) 5-chloro-2-(4,4-difluorobut-3-enylthio)-4-methylthiazole (CompoundVII.27). M⁺ =255; ¹ H NMR: δ 2.35(3H,s); 2.42(2H,m); 3.18(2H,t);4.26(1H,m); (oil) from 2-amino-5-chloro-4-methylthiazole.

EXAMPLE VII.6

This Example illustrates a two-step preparation of ethyl5-bromo-2-(4,4-difluorobut-3-enylthio)thiazole-4-carboxylate (CompoundVII.11).

Step 1: Preparation of ethyl 2-amino-5-bromothiazole-4-carboxylate

Ethyl 2-aminothiazoles-4-carboxylate (5.0 g) (prepared from ethylbromopyruvate and thiourea by the procedure described in J. Med. Chem.,1971, 14, 1075 for the corresponding oxazole) in concentratedhydrobromic acid (9 cm³) was stirred at ambient temperature and treateddropwise with bromine (3.2 g), then heated to 60° C. for 2 hours,neutralised with sodium carbonate and the product extracted into ethylacetate. The organic phase was dried (MgSO₄) and evaporated underreduced pressure to give ethyl 2-amino-5-bromothiazole-4-carboxylate(1.54 g). MH⁺ =251; ¹ H NMR: δ 1.40(3H,t); 4.40(2H,t); 5.6(2H,br s).

Step 2: Preparation of Compound VII.11

The product from Step 1 was treated in a diazotisation reaction, asdescribed in Example VII.5 above and gave Compound VII.11; M⁺ =357; ¹ HNMR: δ 1.40(3H,t); 2.50(2H,m); 3.30(2H,t); 4.30(1H,m); 4.45(2H,q);(oil).

EXAMPLE VII.7

This Example illustrates a three-step preparation of N,N-diethyl2-(4,4-difluorobut-3-enylthio)-4-methylthiazole-5-sulfonamide (CompoundVII.56).

Step 1: N,N-Diethyl 2-acetamido-4-methylthiazole-5-sulfonamide

2-Acetamido-4-methylthiazole-5-sulfonyl chloride (5.2 g) intetrahydrofuran (100 cm³) was stirred at ambient temperature and treatedportionwise with diethylamine (4.5 cm³). The mixture was stirred for 4hours, evaporated under reduced pressure and the residue extracted intoethyl acetate (200 cm³), washed with water (2×100 cm³), dried (MgSO₄)and re-evaporated under reduced pressure to give N,N-diethyl2-acetamido-4-methylthiazole-5-sulfonamide (4.9 g). ¹ H NMR: δ1.20(6H,t); 2.28(3H,s); 2.57(3H,s); 3.32(4H,q); 9.7(1H,br s); (solid).

Step 2: N,N-Diethyl 2-amino-4-methylthiazole-5-sulfonamide

The product from Step 1 (2.5 g) was dissolved in methanol (25 cm³) andcooled to 5° C. with stirring under an atmosphere of nitrogen. Sodiummethoxide in methanol (2 cm³ of 25% wt./vol. solution) was addeddropwise and the mixture allowed to warm to the ambient temperature for18 hours. The reaction was heated under reflux for 1 hour, cooled,diluted with water (250 cm³), extracted with diethyl ether (2×100 cm³),dried (MgSO₄) and evaporated under reduced pressure to give N,N-diethyl2-amino-4-methylthiazole-5-sulfonamide (0.48 g). M⁺ 249; ¹ H NMR: δ1.20(6H,t); 2.48(3H,s); 3.28(4H,q); 5.25(2H,br s); (solid).

Step 3; preparation of Compound VII.56

The product from Step 2 was treated in a diazotisation reaction, asdescribed in Example VII.5 above and gave Compound VII.56; M⁺ =356; ¹ HNMR: δ 1.15(6H,t); 2.45(2H,m); 2.60(3H,s); 3.25(2H,t); 3.26(4H,q);4.25(1H,m); (oil).

EXAMPLE VII.8

This Example illustrates a preparation of2-amino-5-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.128)

4,4-Difluorobut-3-enylisothiouronium hydrobromide (16.87 g) was added toa solution of potassium hydroxide (18.0 g) in ethanol (150 cm³) atambient temperature and stirred for 0.2 hours under an atmosphere ofnitrogen 2-Amino-5-bromothiazole hydrobromide (17.76 g) in ethanol (150cm³) was added in portions, the mixture heated to 40° C. for 2 hours,neutralised with hydrochloric acid and evaporated under reducedpressure. The residue was dissolved in 2M hydrochloric acid, extractedwith diethyl ether, basified with 2M sodium hydroxide and re-extractedwith diethyl ether. The latter ether extracts were combined, dried(MgSO₄) and evaporated under reduced pressure to give Compound VII.128(8.0 g). M⁺ =222; ¹ H NMR: δ 2.28(2H,m); 2.67(2H,t); 4.24(1H,m);5.3(2H,two br s); 7.08(1H,s); (mp 34.6-35.4° C.).

EXAMPLE VII.9

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.82).

Compound VII.128 (0.30 g) was dissolved in dry tetrahydrofuran (14 cm³)and heated under reflux in an atmosphere of nitrogen. Tert. butylnitrite (0.52 cm³) in tetrahydrofuran (8 cm³) was added dropwise over0.25 hours, the mixture heated for 2 hours, further tert. butylnitrite(0.52 cm³) added and heating continued for a further 2 hours. Thesolution was cooled, evaporated under reduced pressure and the residuefactionated by chromatography (silica; eluant hexane: ethyl acetate 1:1by volume) to give Compound VII.128 (0.10 g) ¹ H NMR: δ 2.28(2H,m);2.82(2H,t); 4.24(1H,m); 7.86(1H,s); 8.86(1H,s); (oil).

EXAMPLE VII.10

This Example illustrates a preparation of2-chloro-5-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.114).

Compound VII.128 (4.0 g) in acetonitrile (50 cm³) was added at 0° C. toa stirred mixture of copper(II) chloride (5.38 g) and tert. butylnitrite (3.71 g) in acetonitrile (50 cm³) and allowed to slowly warm toambient temperature over 18 hours. The solvent was evaporated underreduced pressure, the product dissolved in diethyl ether, filtered andthe filtrate re-evaporated to give a yellow-brown liquid which wasfactionated by chromatography (silica; eluant hexane: diethyl ether 4:1by volume) to give Compound VII.114 (2.43 g). M⁺ =241; ¹ H NMR: δ2.28(2H,m); 2.68(2H,t); 4.22(1H,m); 7.52(1H,s) (oil).

EXAMPLE VII.11

This Example illustrates a preparation of2-(4-cyanophenoxy)-5-(4,4-difluorobut-3-enylthio) thiazole (CompoundVII.130).

Compound VII.114 (0.483 g), 4-cyanophenol (0.238 g), anhydrous potassiumcarbonate (0.276 g) and cesium fluoride (0.304 g) inN-methylpyrrolidin-2-one (3 cm³) were stirred together under anatmosphere of nitrogen and heated to 90° C. for 36 hours. The reactionmixture was diluted with water, the product extracted into diethylether, dried (MgSO₄), evaporated under reduced pressure and the residuefractionated by thick layer chromatography (silica; eluted with hexane:diethyl ether 4:1 by volume) to give Compound VII.130 (0.125 g). M⁺=324; ¹ H NMR: δ 2.28(2H,m); 2.80(2H,t); 4.20(1H,m); 7.40(2H,m);7.75(2H,m); (oil).

EXAMPLE VII.12

This Example illustrates a preparation of ethyl5-(4,4-difluorobut-3-enylthio)-thiazole-4-carboxylate (Compound VII.98).

Ethyl isocyanoacetate (2.3 g) in dry tetrahydrofuran (15 cm³) was addedto a stirred mixture of potassium tert. butoxide (2.24 g) at -40° C.under an atmosphere of nitrogen. After 10 minutes the reaction wascooled to -78° C. and carbon disulfide (1.52 g) in tetrahydrofuran (20cm³) was added slowly. On complete addition the reaction temperature wasallowed to rise to -10° C. and 4,4-difluorobut-3-enyl4-methyl-benzenesulfonate (5.24 g) in tetrahydrofuran (10 cm³) wasadded. The mixture was allowed to warm to ambient temperature and wasstirred for 24 hours, heated to reflux for 3 hours and cooled to ambienttemperature. The reaction mixture was poured into aqueous 2Mhydrochloric acid and product was extracted into ethyl acetate. Theorganic phase was dried (MgSO₄) and solvent removed by evaporation underreduced pressure. Column chromatography of the residue on silica gel,eluting with 1:1 hexane: ethyl acetate gave Compound VII.98 (3.15 g). ¹H NMR: δ 1.45(3H,t); 2.50(2H,m); 3.10(2H,t); 4.3-4.4(1H,m); 4.50(2H,q);8.65(1H,s); (oil).

EXAMPLE VII.13

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylthio)-thiazole-4-carboxamide (Compound VII.94).

Compound VII.98 (0.5 g) in methanol (8 cm³) was stirred with aqueousammonia (35 cm³ ; density 0.88) for 4 hours. Compound VII.94 wasobtained as a solid which was filtered from solution and sucked todryness (0.27 g). ¹ H NMR: δ 2.50(2H,m); 3.00(2H,t); 4.30-4.41(1H,m);5.5 and 7.0(2H,broad); 8.55(1H,s); (solid mp 140-141° C.).

The following compounds according to the invention were prepared fromthe corresponding esters using the above procedure:

(i) 2-(4,4-difluorobut-3-enylthio)thiazole-4-carboxamide (CompoundVII.7). M⁺ =250; ¹ H NMR: δ 2.50(2H,m); 3.27(2H,t); 4.28(1H,m); 5.9 and7.1(2H,br s); 8.03(1H,s); (mp 57-58° C.) from Compound VII.8.

(ii) 2-(4,4-difluorobut-3-enylthio)-4-methylthiazole-5-carboxamide(Compound VII.36). ¹ H NMR: δ 2.48(2H,m); 2.66(3H,s) 3.26(2H,t);3.85(3H,s); 4.28(1H,m); 5.7(2H,br s); (mp 99-100° C.) from CompoundVII.41.

EXAMPLE VII.14

This Example illustrates a preparation of4-cyano-5-(4,4-difluorobut-3-enylthio)-thiazole (Compound VII.90).

Compound VII.94 (0.27 g) in dry dichloromethane (13 cm³) was treatedwith pyridine (1 cm³) and methane sulfonyl chloride (0.26 cm³). Themixture was stirred for 5 days, further methane sulfonyl chloride (0.2cm³) added and again stirred for 2 hours. The reaction was then pouredinto aqueous 2M hydrochloric acid and the product was extracted intoethyl acetate. The organic phase was dried (MgSO₄) and evaporated underreduced pressure. Chromatography of the residue on silica gel gaveCompound VII.90 (0.142 g). ¹ H NMR: δ 2.40(2H,m); 3.20(2H,t);4.30(1H,m); 8.80(1H,s).

The following compounds according to the invention were prepared fromthe corresponding carboxamides using the above procedure:

(i) 4-cyano-2-(4,4-difluorobut-3-enylthio)thiazole (Compound VII.6). ¹ HNMR: δ 2.50(2H,m); 3.32(2H,t); 4.26(1H,m); 7.86(1H,s); (oil) fromCompound VII.7.

(ii) 5-cyano-2-(4,4-difluorobut-3-enylthio)-4-methylthiazole (CompoundVII.32). ¹ H NMR: δ 2.48(2H,m); 2.58(3H,s) 3.30(2H,t); 3.85(3H,s);4.28(1H,m); (oil) from Compound VII.36.

EXAMPLE VII.15

This Example illustrates a preparation of5-bromo-2-(4,4-difluorobut-3-enylthio)thiazole-4-caboxylic acid(Compound VII.13).

Compound VII.11 (0.30 g) in methanol (5 cm³) containing aqueous sodiumhydroxide (1.2 cm³ of a 2M solution) was stirred at ambient temperaturefor 18 hours, poured into water and acidified with 2M hydrochloric acidThe product was extracted into ethyl acetate, dried MgSO₄) andevaporated under reduced pressure to give Compound VII.13 (0.18 g). M⁺=329; ¹ H NMR: δ 2.48(2H,m); 3.30(2H,t); 4.28(1H,m); 7.0(1H,broadsignal); (mp 86.5-87.5° C.

The following compounds according to the invention were prepared fromthe corresponding esters using the above procedure:

(i) 2-(4,4-difluorobut-3-enylthio)thiazole-4-carboxylic acid (CompoundVII.10). M⁺ =251; ¹ H NMR: δ 2.50(2H,m); 3.35(2H,t); 4.28(1H,m);8.18(1H,s); (mp 114-15° C.) Compound VII.8.

(ii) 2-(4,4-difluorobut-3-enylthio)-4-methylthiazole-5-carboxylic acid(Compound VII.45). M⁺ =265; ¹ H NMR: δ 2.50(2H,m); 2.70(3H,s);3.27(2H,t); 4.28(1H,m); 9.8(1H,broad signal); (mp 52.0-53.5° C.) fromCompound VII.41.

(iii) 5-(4,4-difluorobut-3-enylthio)thiazole-4-carboxylic acid (CompoundVII.102). M⁺ =251; ¹ H NMR: δ 2.50(2H,m); 3.10(2H,t); 4.28(1H,m);8.70(1H,s); (mp 128.5° C.) from Compound VII.98.

EXAMPLE VII.16

This Example illustrates methods suitable for the preparation ofcompounds according to the invention in which the sulfur atom of the4,4-difluorobut-3-enylthio substituent of the corresponding unoxidisedcompound is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).

Method A: Using potassium peroxymonosulfate as oxidant.

Preparation of 5-chloro-2-(4,4-difluorobut-3-enylsulfonyl)thiazole(Compound VII.26)

A stirred solution of Compound VII.24 (4.83 g) in methanol (50 cm³) at8° C. was treated dropwise with potassium peroxymonosulfate (27.0 g) inwater (100 cm³) with cooling over 0.25 hours, and further methanol (50cm³) added. The reaction was stirred for 18 hours at ambienttemperature, the insolubles filtered from solution, the filtrateextracted with dichloromethane (4×50 cm³) and dried (MgSO₄). The solventwas removed under reduced pressure and the residue fractionated bychromatography (silica; eluant hexane:ethyl acetate 4:1 by volume) togive Compound VII.26 (3.91 g). M(NH4)⁺ =291; ¹ H NMR: δ 2.60(2H,m);3.50(2H,t); 4.25(1H,m); 7.85(1H,s); (oil).

Method B: Using monomagnesium peroxyphthalic acid

Preparation of 5-bromo-2-(4,4-difluorobut-3-enylsulfinyl)thiazole(Compound VII.15).

Compound VII.14 (1.50 g) was dissolved in dichloromethane (10 cm³) andtreated with monomagnesium peroxyphthalic acid hexahydrate (1.6 g, 80%per acid) and water (15 cm³). The mixture was stirred at ambienttemperature for 1 hour, diluted with dichloromethane (90cm³) and theorganic phase washed with aqueous sodium hydrogen carbonate and water.The organic phase was dried (MgSO₄), evaporated under reduced pressureand the residue factionated by chromatography (silica; eluant hexane:ethyl acetate 10:1 by volume) to give Compound VII.15 (1.0g). M(NH4)⁺=321; ¹ H NMR: δ 2.38 (1H,m); 2.60(1H,m); 3.20(2H,m); 4.20(1H,m);7.85(1H,s); (oil).

The following compounds according to the invention were prepared fromthe corresponding thioethers using the above procedure, Method B.

(i) 2-(4,4-difluorobut-3-enylsulfinyl)thiazole (Compound VII.2). MH⁺=224; ¹ H NMR: δ 2.36(1H,m); 2.50-2.70(1H,m); 3.20(2H,m); 4.22(1H,m);7.67(1H,d); 7.98(1H,d); (oil) from Compound VII.1 and one equivalent ofoxidant.

(ii) 2-(4,4-difluorobut-3-enylsulfonyl)thiazole (Compound VII.3). MH⁺=240; ¹ H NMR: δ 2.55(2H,m); 3.45(2H,t); 4.24(1H,m); 7.78(1H,d);8.08(1H,d); (oil) from Compound VII.1 and two equivalents of oxidant.

(iii) 5-bromo-2-(4,4-difluorobut-3-enylsulfonyl)thiazole (CompoundVII.16). M(NH4)⁺ =335; ¹ H NMR: δ 2.58(2H,m); 3.46(2H,t); 4.25(1H,m);7.96(1H,s); (oil) from Compound VII.14 and two equivalents of oxidant.

(iv) 2-(4,4-difluorobut-3-enylsulfinyl)-5-methylthiazole (CompoundVII.22). ¹ H NMR: δ 2.38(1H,m); 2.50-2.65(4H,m); 3.15(1H,m); 4.23(1H,m);7.60(1H,q); (oil) from Compound VII.21 and one equivalent of oxidant.

(v) 2-(4,4-difluorobut-3-enylsulfonyl)-5-methylthiazole (CompoundVII.23). ¹ H NMR: δ 2.55(2H,m); 2.60(3H,s); 3.45(2H,t); 4.25(1H,m);7.73(1H,q); (oil) from Compound VII.21 and two equivalents of oxidant.

(vi) 5-chloro-2-(4,4-difluorobut-3-enylsulfinyl)thiazole (CompoundVII.25). M(NH4)⁺ =275; ¹ H NMR: δ 2.38(1H,m); 2.60(1H,m); 3.18(2H,m);4.25(1H,m); 7.74(1H,s); (oil) from Compound VII.24 and one equivalent ofoxidant.

(vii) 5-(4,4-difluorobut-3-enylsulfinyl)thiazole (Compound VII.83). ¹ HNMR: δ 2.50(2H,m); 3.05(1H,m); 3.20(1H,m); 4.28(1H,m); 8.20(1H,s);9.12(1H,s); (oil) from Compound VII.82 and one equivalent of oxidant.

(viii) 5-(4,4-difluorobut-3-enylsulfonyl)thiazole (Compound VII.84). ¹ HNMR: δ 2.50(2H,m); 3.30(2H,m); 4.25(1H,m); 8.20(1H,s); 9.12(1H,s); (oil)from Compound VII.82 and two equivalents of oxidant.

(ix) 2chloro-5-(4,4-difluorobut-3-enylsulfinyl)thiazole (CompoundVII.115). ¹ H NMR: δ 2.50(2H,m); 3.05(1H,m); 3.20(1H,m); 4.28(1H,m);7.85(1H,s); (oil) from Compound VII.114 and one equivalent of oxidant.

(x) 2-chloro-5-(4,4-difluorobut-3-enylsulfonyl)thiazole (CompoundVII.116). ¹ H NMR: δ 2.52(2H,m); 3.30(2H,m); 4.28(1H,m); 8.08(1H,s);(oil) from Compound VII.114 and two equivalents of oxidant.

Method C: Using 3-chloroperbenzoic acid

The following compounds according to the invention were prepared fromthe corresponding thioethers using the above procedure, Method B, butwith 3-chloroperbenzoic acid in place of monomagnesium peroxyphthalicacid hexahydrate.

(xi) ethyl 2-(4,4-difluorobut-3-enylsulfonyl)thiazole-4-carboxylate(Compound VII.9). M⁺ =311; ¹ H NMR: δ 1.43(3H,t); 2.60(2H,m);3.56(2H,t); 4.28(1H,m); 4.48(2H,q); 8.50(1H,s); (mp 64-65° C.) fromCompound VII.8 and two equivalents of oxidant.

(xii) ethyl5-bromo-2-(4,4-difluorobut-3-enylsulfonyl)thiazole-4-carboxylate(Compound VII.12). M⁺ =389; ¹ H NMR: δ 1.43(3H,t); 2.60(2H,m);3.56(2H,t); 4.28(1H,m); 4.48(2H,q); (mp 72-73° C.) from Compound VII.11and two equivalents of oxidant.

(xiii) 5-chloro-2-(4,4-difluorobut-3-enylsulfonyl)-4-methylthiazole(Compound VII.28). ¹ H NMR: δ 2.55(2H,m); 2.45(3H,s); 3.40(2H,t);4.25(1H,m); (oil) from Compound VII.27 and two equivalents of oxidant.

(xiv) methyl2-(4,4-difluorobut-3-enylsulfonyl)-4-methylthiazole-5-carboxylate(Compound VII.43). ¹ H NMR: δ 2.60(2H,m); 2.85(3H,s); 3.50(2H,t);3.95(3H,s); 4.25(1H,m); (oil) from Compound VII.41 and two equivalentsof oxidant.

(xv) 2-(4,4-difluorobut-3-enylsulfonyl)-4-methylthiazole-5-sulfonylfluoride (Compound VII.53). ¹ H NMR: δ 2.60(2H,m); 2.85(3H,s);3.55(2H,t); 4.28(1H,m); (mp 67° C.) from Compound VII.52 and twoequivalents of oxidant.

EXAMPLE VIII.1

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-1-methylimidazol (Compound VIII.5).

To a solution of 2-mercapto-1-methylimidazole (9.78 g) in acetone (300cm³) was added potassium carbonate (14.2 g) and4-bromo-1,1-difluorobut-1-ene (16.12 g) as a solution in acetone(100cm³). The mixture was heated at reflux for 18 hours and allowed tocool. Inorganic solids were removed by filtering the reaction mixturethrough a plug of sorbsil-C30 silica, washing with ethyl acetate. Thefiltrate was evaporated under reduced pressure to give crude CompoundVIII.5 (17.8 g), which was suitable for further reaction (see ExampleVIII.7).

A portion (1 g) was purified by chromatography on sorbsil C-30, elutingwith ethyl acetate: hexane 3:7, and gave pure Compound VIII.5 (0.776 g).¹ H NMR: δ 2.3-2.4(2H,m); 3.05-3.15(2H,t); 3.60(3H,s); 4.15-4.35(1H,m);6.95(1H,s); 7.05(1H,s); (oil).

The following compounds according to the invention were prepared by theabove procedure, using the appropriate mercapto imidazole:

(i) 2-(4,4-difluorobut-3-enylthio)-1-phenylimidazole (Compound VIII.3).M⁺ =266; ¹ H NMR: δ 2.3-2.4(2H,m); 3.1-3.15(2H,t); 4.1-4.25(1H,m);7.1-7.2(2H,m); 7.3-7.55(5H,m); (oil).

(ii) 2-(4,4-difluorobut-3-enylthio)-1-ethylimidazole (Compound VIII.10).M⁺ =218; ¹ H NMR: δ 1.4(3H,t); 2.3-2.4(2H,m); 3.15(2H,t); 4.0(2H,q);4.2-4.35(1H,m); 6.95(1H,s); 7.1(1H,s); (oil).

(iii) 2-(4,4-difluorobut-3-enylthio)-4-ethyl-5-methylimidazole (CompoundVIII.27). M⁺ =232; ¹ H NMR: δ 1.15(3H,t); 2.15(3H,s); 2.35-2.45(2H,m);2.5-2.6(2H,q) 2.95(2H,t); 4.1-4.3(1H,m); (m.p. 54-56° C.).

(iv) 2-(4,4-difluorobut-3-enylthio)-4-methylimidazole (CompoundVIII.58). M⁺ =204; ¹ H NMR: δ 2.25-2.35(5H,m); 3.0(2H,t);4.15-4.3(1H,m); 6.75(1H,s); (oil).

(v) 2-(4,4-difluorobut-3-enylthio)-4-ethoxycarbonylimidazole (CompoundVIII.64). M⁺ =262; ¹ H NMR: δ 1.3-1.35(3H,t); 2.25-2.35(2H,m);3.05-3.15(2H,t); 4.1-4.25(1H,m); 4.3-4.4(2H,q); 7.8(1H,br s); (mp57.8-61° C.).

(vi) 3-(4,4-difluorobut-3-enylthio)imidazo- 1,5a!-pyridine (CompoundVII.151). ¹ H NMR: δ 2.30 (2H,m); 3.00(2H,t); 4.20(1H,m); 6.65(1H,m);6.80(1H,m); 7.45(1H,dt); 7.55(1H,s); 8.15(1H,dd); (oil) from2,3-dihydroimidazo 1,5a!-pyridine-3-thione.

EXAMPLE VIII.2

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-imidazole (Compound VIII.1) and1-(4,4-difluorobut-3-enyl)-2-(4,4-difluorobut-3-enylthio)imidazole(Compound VIII.8) as a mixture of products separable by chromatography.

To a solution of 2-mercapto-imidazole (10.01 g) in acetone (400 cm³) wasadded potassium carbonate (20.73 g) and 4-bromo-1,1-difluorobut-1-ene(18.79 g). The mixture was heated at reflux for 18 hours and allowed tocool. Inorganic solids were removed by filtering the reaction mixturethrough a plug of sorbsil-C30 silica, washing with ethyl acetate. Thefiltrate was evaporated under reduced pressure to give a pale browm oil(19.2 g) which was chromatographed on silica, eluting with 15% ethylacetate in hexane, progressing to 50% ethyl acetate in hexane. Two mainfractions were obtained, the first of which (7.4 g) was shown by tlc tocontain two products. The second fraction (10.75 g), obtained as a whitesolid, was shown to be pure Compound VIII.1. The first fraction wassubjected to further chromatography as before to give Compound VIII.8(1.61 g); M⁺ =280; ¹ H NMR: δ 2.3-2.45(4H,m); 3.1-3.15(2H,t);3.9-4.0(2H,t); 4.05-4.3(2H,m); 6.95(1H,s); 7.05(1H,s); (oil) andCompound VIII.1 (5.31 g). This sample of Compound VIII.1 wasrecrystallised from ethyl acetate and hexane to provide 4.2 g which hadM⁺ =190; ¹ H NMR: δ 2.3-2.4(2H,m); 3.0-3.1(2H,t); 4.15-4.3(1H,m);7.0-7.1(2H,br s); 9.2(1H,br s); (mp. 58.6-59.6° C.).

EXAMPLE VIII.3

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-4-phenylimidazole (Compound VIII.19).

Phenacyl bromide (1.611 g) in chloroform (7 cm³) was added to4,4-difluorobut-3-enylisothiouronium hydrobromide (2 g) in 84%ethanol/water (20 cm³) and sodium bicarbonate (2.72 g) was slowly addedwith stirring. The resultant yellow suspension was heated under refluxfor 3 hours. The mixture was cooled and solvent was removed byevaporation under reduced pressure. The residue was washed twice withwarm water (2×20 cm³) which was decanted off to remove inorganicmaterial. The crude product so obtained was purified by chromatographyon silica, eluting with 20% ethyl acetate in hexane, andproduct-containing factions were recolumned using 5% ethyl acetate intoluene. This gave Compound VIII.19 (0.78 g); M⁺ =266; ¹ H NMR: δ2.3-2.4(2H,m); 3.05-3.1(2H,t); 4.15-4.3(1H,m); 7.2-7.4(4H,m);7.6-7.75(2H,br s) free of a byproduct, the corresponding N-phenacylderivative.

The following compounds according to the invention were prepared by theabove procedure:

(i) 2-(4,4-difluorobut-3-enylthio)-1-methyl-4-phenylimidazole (CompoundVIII.22). M⁺ =280; ¹ H NMR: δ 2.35-2.45(2H,m); 3.10-3.18(2H,t);3.65(3H,s); 4.19-4.35(1H,m); 7.2-7.25(2H,m); 7.33-7.38(2H,t);7.72-7.78(2H,d) (oil) using N-methyl4,4-difluorobut-3-enylisothiouronium hydrobromide.

(ii)2-(4,4-difluorobut-3-enylthio)-5-ethyl-4-methoxycarbonyl-1-methylimidazole(Compound VIII.68). M⁺ =290; ¹ H NMR: δ 1.2-1.25(3H,t); 2.35-2.45(2H,m);2.8-2.9(2H,q); 3.2-3.25(2H,t); 3.78(3H,s); 3.85(3H,s); 4.16-4.32(1H,m);(oil) using N-methyl 4,4-difluorobut-3-enylisothiouronium hydrobromideand methyl 2-bromo-3-oxopentanoate.

EXAMPLE VIII.4

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-4,5-dimethylimidazole (Compound VIII.29).

Potassium carbonate (18.9 g) and 4,4-difluorobut-3-enylisothiouroniumhydrobromide (16.9 g) were added to a solution of 3-bromobutan-2-one(10.32 g) in dimethyl formamide (100 cm³) and the mixture was stirred at60° C. for 90 minutes, then at 80° C. for 30 minutes. The resultingmixture was cooled, water (100 cm³) added, and the product enacted intodiethyl ether. The combined organic phases were washed with water andbrine and dried (MgSO₄). Concentration by evaporation under reducedpressure gave a pale orange liquid (12.2 g), which was purified bychromatography on sorbsil C30 silica, eluting with 30% ethyl acetate inhexane. Three components were obtained. The first eluted was identifiedas 3-(4,4-difluorobut-3-enylthio)butan-2-one (0.68 g); M⁺ =194; ¹ H NMR:δ 1.4(3H,d); 2.15-2.3(5H,m); 2.45(2H,t); 3.3-3.4(1H,q); 4.1-4.35(1H,m).The second compound eluted was the desired Compound VIII.29 (4.1 g); M⁺=218; ¹ H NMR: δ 2.15(6H,s) 2.25-2.35(2H,m); 2.9-3.0(2H,t);4.15-4.3(1H,m); (mp 81.4-84.4° C.). The third compound eluted wasidentified as the product of a further N-alkylation of Compound VIII.29with additional 3-bromobutan-2-one, namely N-(1-methylpropan-2-one)2-(4,4-difluorobut-3-enylthio)-4,5-dimethylimidazole (1.11 g); M⁺ =217;¹ H NM: δ 1.55(3H,s); 2.0(3H,s); 2.05(3H,s); 2.15(3H,s); 2.3-2.4(2H,m);3.0-3.05(2H,t); 4.15-4.35(1H,m); 5.0-5.1(1H,m); (oil).

EXAMPLE VIII.5

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-1-propylimidazole (Compound VIII.12) fromthe corresponding N-H imidazole, Compound VIII.1, by alkylation usingpropyl iodide.

Compound VIII.1 (2 g) was added in portions (effervescence) to asuspension of sodium hydride (0.736 g of a 60% solid in oil) in dimethylformamide (20 cm³) under a nitrogen atmosphere. After stirring themixture for 30 minutes, n-propyl iodide (2.68 g) was added and thereaction mixture was stirred at the ambient temperate for 18 hours.Water and diethyl ether were then added and the product extracted intoether. The combined organic phases were washed with water and saturatedbrine and dried (NgSO₄). After filtration, the solvent was removed byevaporation under reduced pressure to give crude product (2.7 g) whichwas purified by chromatography on sorbsil C-30, eluting with ethylacetate: hexane 3:7 and gave Compound VIII.12 (2.15 g); M⁺ =232; ¹ HNMR: δ 0.9-0.95(3H,t); 1.75-1.85(2H,m); 2.3-2.45(2H,m); 3.1-3.15(2H,t);3.85-3.95(2H,t);4.15-4.35(1H,m); 6.9(1H,s); 7.1(1H,s); (oil).

The following compounds according to the invention were prepared by theabove procedure, using the appropriate alkylating agent and starting N-Himidazole:

(i) 2-(4,4-difluorobut-3-enylthio)-1-(1-methylethyl)-imidazole (CompoundVIII.14). M⁺ =232; ¹ H NMR: δ 1.4(6H,d); 2.3-2.4(2H,m); 3.1-3.15(2H,t);4.15-4.3(1H,m); 4.5-4.6(1H,m); 7.0(1H,s); 7.1(1H,s); (oil) from CompoundVIII.1.

(ii) 2-(4,4-difluorobut-3-enylthio)-1,4,5-trimethylimidazole (CompoundVIII.31). ¹ H NMR: δ 2.15(6H,two s); 2.25-2.35(2H,m); 2.95(2H,t);3.5(3H,s); 4.15-4.3(1H,m); (oil) from Compound VIII.29.

(iii) 1-ethyl-2-(4,4-difluorobut-3-enylthio)-4,5-dimethylimidazole(Compound VIII.33). ¹ H NMR: δ 1.25(3H,t); 2.15(6H,br s); 2.3-2.4(2H,m);3.0(2H,t); 3.9-3.95(2H,q); 4.15-4.3(1H,m); (oil) from Compound VIII.29.

(iv) A mixture of 2-(4,4-difluorobut-3-enylthio)1,5-dimethylimidazole(Compound VIII.35) and2-(4,4-difluorobut-3-enylthio)-1,4-dimethylimidazole (Compound VIII.60);¹ H NMR: δ 2.15(3H,s); 2.3-2.4(2H,m); 3.0-3.05(2H,t); 3.5 and3.55(3H,two s); 4.15-4.3(1H,m); 6.65 and 6.80(1H,two s) from CompoundVIII.58.

(v) A mixture of2-(4,4-difluorobut-3-enylthio)-5-methyl-1-(1-methylethyl)-imidazole(Compound VIII.37) and2-(4,4-difluorobut-3-enylthio)-4-methyl-1-(1-methylethyl)-imidazole(Compound VIII.62); shown to be mainly the latter isomer, ¹ H NMR: δ1.35(6H,d); 2.2(3H,s); 2.3-2.4(2H,m); 3.05(2H,t); 4.15-4.3(1H,m);4.5-4.6(1H,m); 6.70(1H,s) from Compound VIII.58.

(vi) 2-(4,4-difluorobut-3-enylthio)-5-ethoxycarbonyl-1-methylimidazole(Compound

VIII.52). M⁺ =276; ¹ H NMR: δ 1.32-1.40(3H,t); 2.37-2.47(2H,m);3.2-3.3(2H,t); 3.82(3H,s); 4.17-4.32(1H,m); 4.25-4.35(2H,q); 7.7(1H,s);(oil) from Compound VIII.64. This reaction produced achromatographically separable mixture of Compound VIII.52 and VIII.65,the former eluting first.

(vii) 2-(4,4-difluorobut-3-enylthio)-4-ethoxycarbonyl-1-methylimidazole(Compound VIII.65). M⁺ =276; ¹ H NMR: δ 1.35-1.40(3H,t);2.35-2.42(2H,m); 3.20-3.27(2H,t); 3.63(3H,s); 4.15-4.30(1H,m);4.3-4.4(2H,q); 7.60(1H,s); (oil) from Compound VIII.64.

EXAMPLE VIII.6

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-N-(methane sulfonyl)imidazole (CompoundVIII.18).

A solution of Compound VIII.1 (0.49 g) in dry tetrahydrofuran (3 cm³)was added dropwise to a suspension of sodium hydride (55% in oil, 0.12g, washed with hexane prior to use) in dry tetrahydrofuran (5cm³) cooledin a cold water bath. The reaction mike was allowed to stir at theambient temperature for 2 hours and then methanesulfonylchloride (0.3 g)was added and the reaction sired for a further 16 hours. The reactionmixture was poured into ethyl acetate/water and the layers separated.The aqueous layer was extracted with ethyl acetate and the combinedorganic phases were dried (MgSO₄), filtered and evaporated under reducedpressure to give a yellow oil. Purification by column chromatography onsilica gel using 3:7 ethyl acetate:hexane gave Compound VIII.18 (0.31g). ¹ H NMR: δ 2.40-2.50(2H,m); 3.30 (2H,t); 3.30(3H,s); 4.25(1H,m);7.05(1H,d); 7.35(1H,d); (oil).

EXAMPLE VIII.7

This Example illustrates a method suitable for the preparation ofcompounds according to the invention in which the sulfur atom of the4,4-difluorobut-3-enylthio substituent of the corresponding unoxidisedcompound is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).

Preparation of Compound VIII.7 from Compound VIII.5.

Compound VIII.5 (18.1 g) was cooled to 0° C. in dichloromethane (400cm³) and 3-chloroperbenzoic acid (61.2 g of water-wet solid, 2 equiv.)was added. The mixture was stirred at the ambient temperature for 18hours and then poured into saturated aqueous sodium bicarbonate. Theproduct was extracted into dichloromethane, the organic phase washedwith water and sanded brine and dried (MgSO₄). Evaporation of solventunder reduced pressure gave crude Compound VIII.7 which waschromatographed on silica, eluting with 15% ethyl acetate in hexane,progressing to 50% ethyl acetate in hexane, to give pure CompoundVIII.7. ¹ H NMR: δ 2.55-2.6(2H,m); 3.5-3.55(2H,t); 4.0(3H,s);4.15-4.3(1H,m); 7.0(1H,s); 7.15(1H,s); (oil).

The following compounds according to the invention were prepared by theabove procedure of Example VIII., using two equivalents of oxidantunless otherwise specified, with the appropriate starting thioether:

(i) 2-(4,4-difluorobut-3-enylsulfonyl)-imidazole (Compound VIII.2). MH⁺=223; ¹ H NM: δ 2.4-2.6(2H,m); 3.4-3.45(2H,t); 4.1-4.3(1H,m);7.3-7.4(3H,br s); (white solid, m.p. 113-114° C.).

(ii) 2-(4,4-difluorobut-3-enylsulfonyl)-1-phenylimidazole (CompoundVIII.4). M^(+=298;) ¹ H NMR: δ 2.45-2.55(2H,m); 3.45-3.55(2H,t);4.15-4.3(1H,m); 7.2(1H,d); 7.25(1H,d); 7.45-7.55(5H,m); (oil).

(iii)1-(4,4-difluorobut-3-enyl)-2-(4,4-difluorobut-3-enylsulfonyl)-imidazole(Compound VIII.9). M⁺ =312; ¹ H NMR: δ 2.5-2.65(4H,m); 3.5-3.6(2H,t);4.1-4.35(2H,m); 4.4-4.45(2H,t); 7.05(1H,s); 7.15(1H,s); (oil).

(iv) 2-(4,4-difluorobut-3-enylsulfonyl)-1-ethylimidazole (CompoundVIII.11). M⁺ =250; ¹ H NMR: δ 1.5(3H,t); 2.5-2.65(2H,m); 3.5-3.6(2H,t);4.15-4.35(1H,m); 4.4-4.45(2H,q); 7.05(1H,s); 7.15(1H,s); (oil).

(v) 2-(4,4-difluorobut-3-enylsulfonyl)-1-propylimidazole (CompoundVIII.13). M⁺ =265; ¹ H NMR: δ 0.9-1.0(3H,t); 1.8-2.0(2H,m);2.5-2.6(2H,m); 3.5-3.6(2H,t); 4.15-4.35(3H,m); 7.05(1H,s); 7.15(1H,s);(oil).

(vi) 2-(4,4-difluorobut-3-enylsulfonyl)-1-(1-methylethyl)-imidazole(Compound VIII.15). M⁺ =264; ¹ H NMR: δ 1.5(6H,d); 2.55-2.65(2H,m);3.5-3.6(2H,m); 4.15-4.35(1H,m); 5.15-5.35(1H,m); 7.15(2H,br); (oil).

(vii) 2-(4,4-difluorobut-3-enylsulfinyl)-4-phenylimidazole (CompoundVIII.20). M⁺ =282; ¹ H NMR: δ 2.35-2.65(2H,m); 3.25-3.4(2H,t);4.15-4.3(1H,m); 7.25-7.5(4H,m); 7.6-7.8(2H,m); (oil) using 1.5equivalents of oxidant.

(viii) 2-(4,4-difluorobut-3-enylsulfonyl)-4-phenylimidazole (CompoundVIII.21). M⁺ =298; ¹ H NMR: δ 2.45-2.6(2H,m); 3.4-3.5(2H,t);4.1-4.28(1H,m); 7.3-7.55(4H,m); 7.7-7.75(2H,d); (m.p. 109.6-110.4° C.)using 1.5 equivalents of oxidant.

(ix) 2-(4,4-difluorobut-3-enylsulfinyl)-1-methyl-4-phenylimidazole(Compound VIII.23). M⁺ =296; ¹ H NMR: δ 2.5-2.65(2H,m); 3.4-3.65(2H,m);4.0(3H,s); 4.25-4.4(1H,m); 7.25-7.45(4H,m); 7.7-7.75(2H,dd); (m.p.106-106.6° C.) using 1.5 equivalents of oxidant.

(x) 2-(4,4-difluorobut-3-enylsulfonyl)-1-methyl-4-phenylimidazole(Compound VIII.24). M⁺ =312; ¹ H NMR: δ 2.6-2.7(2H,m); 3.58-3.65(2H,t);4.02(3H,s); 4.2-4.35(1H,m); 7.25-7.42(4H,m); 7.7-7.75(2H,dd); (m.p.78.6-79.6° C.) using 1.5 equivalents of oxidant.

(xi) 2-(4,4-difluorobut-3-enylsulfonyl)-4-ethyl-5-methylimidazole(Compound VIII.28). M⁺ =264; ¹ H NMR: δ 1.15-1.3(3H,q); 2.25(3H,two s(tautomers)); 2.45-2.7(4H,m); 3.35-3.45(2H,t); 4.1-4.3(1H,m); 11.3(1H,brs); (oil).

(xii) 2-(4,4-difluorobut-3-enylsulfonyl)-4,5-dimethylimidazole (CompoundVIII.30). M⁺ =250; ¹ H NMR: δ 2.25(6H,two s); 2.45-2.55(2H,m);3.35(2H,t); 4.1-4.25(1H,m); 10.3-10.6(1H,br s); (mp 113.4-114.6° C.).

(xiii) 2-(4,4-difluorobut-3-enylsulfonyl)-1,4,5-trimethylimidazole(Compound VIII.32). M⁺ =264; ¹ H NMR: δ 2.2(6H,br s); 2.5-2.6(2H,m);3.4-3.5(2H,t); 3.85(3H,s); 4.15-4.3(1H,m); (oil).

(xiv) 1-ethyl-2-(4,4-difluorobut-3-enylsulfonyl)-4,5-dimethylimidazole(Compound VIII.34). M⁺ =278; ¹ H NMR: δ 1.4(3H,t); 2.15(6H,br s);2.5-2.6(2H,m); 3.5(2H,t); 4.15-4.3(1H,m); (oil).

(xv) A mixture of2-(4,4-difluorobut-3-enylsulfonyl)-1,5-dimethylimidazole (CompoundVIII.36) and 2-(4,4-difluorobut-3-enylsulfonyl)-1,4-dimethylimidazole(Compound VIII.61); ¹ H NMR: δ 2.20(3H,s); 2.25(3H,s); 2.5-2.6(4H,m);3.45-3.55(4H,m); 3.85(3H,s); 3.95(3H,s); 4.15-4.3(2H, m); 6.75(1H,s);6.95(1H,s); from the mixture Compounds VIII.35 and VIII.60 prepared inExample VIII.5(iv) above.

(xvi) An 18:82 mixture of2-(4,4-difluorobut-3-enylsulfonyl)-5-methyl-1-(1-methylethyl)-imidazole(Compound VIII.38); ¹ H NMR: δ 1.55(6H,d); 2.4(3H,s); 2.55-2.65(2H,m);3.6(2H,t); 4.15-4.35(1H,m); 5.15-5.30(1H,m); 6.85(1H,s); and2-(4,4-difluorobut-3enylsulfonyl)-4-methyl-1-(1-methylethyl)-imidazole(Compound VIII.63); ¹ H NMR: δ 1.45(6H,d); 2.25(3H,s); 2.55-2.65(2H,m);3.55(2H,t); 4.15-4.35(1H,m); 5.15-5.30(1H,m); 6.90(1H,s); from themixture of Compounds VIII.37 and VIII.62 prepared in Example VIII.5(v)above.

(xvii)2-(4,4-difluorobut-3-enylsulfonyl)-5-ethoxycarbonyl-1-methylimidazole(Compound VIII.53). M⁺ =308; ¹ H NMR: δ 1.37-1.42(3H,t);2.55-2.67(2H,m); 3.6-3.65(2H,t); 4.2-4.35(1H,m); 4.25(3H,s);4.32-4.4(2H,q); 7.7(1H,s); (oil).

(xviii) 2(4,4-difluorobut-3-enylsulfonyl)-4-methylimidazole (CompoundVIII.59). M⁺ =236; ¹ H NMR: δ 2.3-2.4(3H,br); 2.45-2.55(2H,m);3.4(2H,t); 4.2-4.4(1H,m); 7.0(1H,br); (oil).

(xix)2-(4,4-difluorobut-3-enylsulfinyl)-4-ethoxycarbonyl-1-methylimidazole(Compound VIII.66). M⁺ =292; ¹ H NMR: δ 1.35-1.4(3H,t); 2.49-2.7(2H,m);3.35-3.6(2H,m); 4.02(3H,s); 4.2-4.38(1H,m); 4.35-4.42(2H,q); 7.67(1H,s);(oil) using 1.5 equivalent of oxidant.

(xx)2-(4,4-difluorobut-3-enylsulfonyl)-4-ethoxycarbonyl-1-methylimidazole(Compound VIII.67). M⁺ =308; ¹ H NMR: δ 1.35-1.4(3H,t); 2.55-2.65(2H,m);3.65-3.70(2H,t); 4.02(3H,s); 4.2-4.38(1H,m); 4.35-4.42(2H,q);7.65(1H,s); (oil) using 1.5 equivalents of oxidant.

(xxi) 3-(4,4-difluorobut-3-enylsulfonyl)imidazo- 1,5a!-pyridine(Compound VIII.152). M⁺ =272; ¹ H NMR: δ 2.50(2H,m); 3.50(2H,t);4.15(1H,m); 6.90(1H,m); 7.10(1H,m); 7.20(1H,s); 7.65(1H,m); 8.95(1H,dd);(oil).

EXAMPLE IX.1

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylthio)-1,3-dimethyl-4-nitropyrazole (CompoundIX.82).

4,4-Difluorobut-3-enylisothiouronium hydrobromide (2.46 g) was stirredat ambient temperature with aqueous sodium hydroxide (1.2 g in 12 cm³water) for 0.3 hours. 5-Chloro-1,3-dimethyl-4-nitropyrazole (1.76 g) indichloromethane (12 cm³) containing tetra-n-butyl ammonium bromide (0.01g; catalyst) was added at ambient temperature and the reaction mixturestirred for 18 hours under an atmosphere of nitrogen. The reaction wasdiluted with water (100 cm³) and the product extracted intodichloromethane (100 cm³). The organic phases were combined, washed withwater, dried (NgSO₄) and evaporated under reduced pressure to give apale yellow liquid (2.6 g). A sample (0.9 g) was fractionated usingchromatography (silica; hexane:ethyl acetate 10:1 by volume) to giveCompound IX.82 (0.78 g). M⁺ =263; ¹ H NMR: δ 2.25(2H,m); 2.55(3H,s);3.08(2H,t); 3.94(3H,s); 4.20(1H,m); (oil).

EXAMPLE IX.2

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylsulfonyl)-1,3-dimethyl-4-nitropyrazole(Compound IX.84).

3-Chloroperbenzoic acid (1.74 g of 50% by weight solid) was added to asolution of Compound IX.82 (0.526 g) in dichloromethane (10 cm³) and thereaction was stirred at ambient temperature for 3 days. The reaction wasdiluted with dichloromethane (100 cm³), washed with aqueous sodiumhydrogen carbonate and then water, dried (MgSO₄) and evaporated underreduced pressure to give an oily solid. The crude product wasfractionated using chromotography to give Compound IX.84 (0.15 g). ¹ HNMR: δ 2.52(3H,m); 2.60(2H,m); 3.74(2H,t); 4.20(3H,s); 4.25(1H,m);(gum).

EXAMPLE IX.3

This Example illustrates a 3-step preparation of5-(4,4-difluorobut-3-enylthio)-1,3-dimethyl-4-iodopyrazole (CompoundIX.61)

Step 1: Preparation of4amino-5-(4,4-difluorobut-3-enylthio)-1.3-dimethylpyrazole

Compound IX.82 (1.0 g) was dissolved in propan-2-ol (10 cm³) containingwater (2 cm³) and concentrated hydrochloric acid (catalyst, 0.1 cm³) andtreated with reduced iron powder (1.0 g). The mixture was stirred andheated under reflux for 3 hours, cooled, neutralised with solid sodiumhydrogen carbonate and filtered through keiselgel. The insolubles werewashed with propan-2-ol, and the filtrate evaporated under reducedpressure to give the amino pyrazole intermediate as a red-brown oil,(1.0 g). M⁺ =233.

Step 2:

The product from Step 1 (4.6 g) was dissolved in dry dichloromethane (25cm³) and added to a stirred solution of boron trifluororide diethyletherate (4.26 g) in dry dichloromethane (25 cm³) at -15° C. Tert. butylnitrite in dichloromethane (10 cm³) was added dropwise to the mixture.The reaction was allowed to warm to 5° C. for 0.3 hours, diluted withhexane and the required diazonium tetrafluoroborate salt was filteredfrom solution as a brown solid (6.7 g).

Step 3: Compound IX.61

The product from Step 1 (1.33 g) was added in portions to a stirredsolution of potassium iodide (1.7 g) in water (5 cm³) at 35° C. Thereaction mixture evolved gas during the process and gave a red-brownoil. After 1 hour at 35° C. the mixture was cooled, diluted with water,extracted with diethyl ether (100 cm³), the organic phase washedsuccessively with aqueous sodium metabisulfite then water and dried(MgSO₄). The solvent was removed under reduced pressure and the residualoil fractionated by chromatography (silica; hexane: ethyl acetate 10:1by volume) to give Compound IX.61 as a brown oil (0.2 g). M⁺ =344.

EXAMPLE IX.4

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylthio)-1,3-dimethyl-pyrazole (Compound IX.55).

The diazonium salt from Example IX.3, Step 2 (2.0 g) was stirred inmethanol (20 cm³) at 0° C. and sodium borohydride (powder, 0.25 g) wasadded in portions. Gas was evolved and the solution changed fromcolourless to orange-brown. The mixture was allowed to warm to 15° C.over 0.5 hours, stored at ambient temperature for 18 hours, diluted withwater, extracted with diethyl ether, dried (MgSO₄) and evaporated underreduced pressure to give a red-brown liquid. The liquid was fractionatedusing chromatography (silica; hexane:diethyl ether 1:1 by volume) togive Compound IX.55 (0.42 g). M⁺ =218; ¹ H NMR: δ 2.20-2.30(5H,m);2.74(2H,m); 3.75(3H,s); 4.23(2H,m); 6.12(1H,s); (oil).

EXAMPLE IX.5

This Example illustrates a preparation of ethyl5-(4,4-difluorobut-3-enylthio)-1-methylpyrazol-4-yl carboxylate(Compound IX.34).

Bis-(4,4-difluorobut-3-enyl)disulfide (2.90 g) and tert. butyl nitrite(1.22 g) in acetonitrile (40 cm³) were heated to 60° C. under anatmosphere of nitrogen. To the stirred solution was added dropwise ethyl5-aminol-1-methylpyrazol-4-yl carboxylate (1.00 g) in acetonitrile (10cm³). On complete addition the reaction solution was heated for 2 hoursat 60° C., evaporated under reduced pressure and fractionated bychromatography (silica; hexane:diethyl ether, 5:1 by volume) to giveCompound IX.34 (yield 42%). M⁺ =276; ¹ H NMR: δ 1.38(3H,t); 2.20(2H,m);3.05(2H,t); 3.97(3H,s); 4.25(1H,m); 4.34(2H,q); 7.98(1H,s); (oil).

The following compounds according to the invention were prepared usingthe above procedure and the appropriate amino-pyrazole:

(i) 4-bromo-5-(4,4-difluorobut-3-enylthio)-1-methylpyrazole (CompoundIX.31). M⁺ =282; ¹ H NMR: δ 2.32(2H,m); 2.95(2H,t); 3.88(3H,s);4.30(1H,m); 7.38(1H,s); (oil).

(ii) 4-cyano-5-(4,4-difluorobut-3-enylthio)-1,3-dimethylpyrazole(Compound IX.73). ¹ H NMR: δ 1.38(3H,t); 2.20(2H,m); 2.38(3H,s);3.02(2H,t); 3.97(3H,s); 4.25(1H,m); (oil).

(iii) ethyl 5-(4,4-difluorobut-3-enylthio)-1-phenylpyrazol-4-ylcarboxylate (Compound IX.124). M⁺ =338; ¹ H NMR: δ 1.40(3H t);2.05(2H,m); 2.88(2H,t); 3.97(1H,m); 4.37(2H,q); 7.50(5H,m); 8.16(1H,s);(oil).

EXAMPLE IX.6

This Example illustrates a preparation of4-cyano-5-(4,4-difluorobut-3-enylsulfonyl)-1, 3-dimethylpyrazole(Compound IX.75).

Compound IX.73 (1.32 g) in dichloromethane (120 cm⁺) was treated atambient temperature with 3-chloroperbenzoic acid (3.94 g containing 50%peracid). The mixture was stirred for 18 hours, diluted with furtherdichloromethane and washed successively with aqueous solutions of sodiumcarbonate, sodium metabisulfite. Further washing with water, sodiumcarbonate, and water were performed before the organic phase was dried(MgSO₄). The solvent was evaporated under reduced pressure and theresidue fractionated by chromatography (silica; hexane:diethyl ether 1:1by volume) to give Compound IX.75 (0.47 g). M⁺ =275; ¹ H NMR: δ2.42(3H,s); 2.30(2H,m); 2.58(3H,s); 3.38(2H,t); 4.14(3H,s); 4.36(1H,m);(mp 78-81° C.).

The following compounds according to the invention were prepared usingthe above procedure and the appropriate pyrazole:

(i) 4-bromo 5-(4,4-difluorobut-3-enylsulfonyl)-1-methylpyrazole(Compound IX.33). ¹ H NMR: δ 2.54(2H,m); 3.35(2H,t); 4.00(3H,s);4.27(1H,m); 7.55(1H,s); (mp 42.6-43.6° C.) from Compound IX.31.

(ii) ethyl5-(4,4-difluorobut-3-enylsulfonyl)-1-methylpyrazole-4-carboxylate(Compound IX.36). ¹ H NMR: δ 1.38(3H,t); 2.50(2H,m); 3.78(2H,t);4.15-4.30(1H,m); 4.36(2H,q); 7.95(1H,s); (oil) from Compound IX.34.

(iii) ethyl5-(4,4-difluorobut-3-enylsulfonyl)-1-phenylpyazole-4-carboxylate(Compound IX.126). ¹ H NMR: δ 1.42(3H,t); 2.45(2H,m); 3.72(2H,t);4.18(1H,m); 4.40(2H,q); 7.35-7.55(5H,m); 8.13(1H,s); (mp 62.5-63.0° C.)from Compound IX.124.

EXAMPLE IX.7

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylthio)-1-methylpyrazole-4carboxylic acid(Compound IX.40) and propan-2-yl5-(4,4-difluorobut-3-enylthio)-1-methylpyrazole-4-carboxylate (CompoundIX.37).

Compound IX.34 (1.5 g) was dissolved in propan-2-ol (40 cm³) and treatedwith 2M aqueous sodium hydroxide (8 cm³) and stirred at ambient templefor 18 hours. The mixture was diluted with water (100 cm³), acidifiedwith 2M aqueous hydrochloric acid and extracted with ethyl acetate (3×50cm³). The combined organic phase was dried (MgSO₄) and evaporated underreduced pressure to give a yellow oil which solidified on treatment withhexane/diethyl ether. The solid was filtered from solution, washed withhexane and sucked to dryness to give Compound IX.40 (0.76 g). ¹ H NMR: δ2.24(2H,m); 3.06(2H,t); 4.00(3H,s); 4.20(1H,m); 8.08(1H,s); (mp59.4-60.0° C.).

The hexane/diethyl ether filtrate was evaporated under reduced pressureand the oil (containing (Compound IX.37 with about 10% of the ethylester starting material from step 1) was treated with propan-2-ol (20cm³) containing sodium methoxide (transesterification catalyst, 10 mg)and the mixture heated under reflux for 5 hours. The reaction wascooled, diluted with water, and product extracted into diethyl ether.The organic phase was dried (MgSO₄) and evaporated under reducedpressure to give Compound IX.37 (0.1 g). M⁺ =291; ¹ H NMR: δ 1.35(6H,d);2.22(2H,m); 3.05(2H,t); 3.97(3H,s); 4.20(1H,m); 5.20(1H, septuplet);7.95(1H,s); (oil).

EXAMPLE IX.8

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylsulfonyl)-1-methylpyrazole-4-carboxylic acid(Compound IX.42).

Compound IX.36 (0.83 g) was dissolved in ethanol (35 cm³) and treatedwith lithium hydroxide monohydrate (0.34 g) in water (7 cm³) at ambienttemperature. The reaction mixture was stirred for 18 hours, the ethanolevaporated under reduced pressure, the aqueous phase acidified with 2Mhydrochloric acid, and product extracted into ethyl acetate. The organicphase was dried (MgSO₄) and solvent was removed under reduced pressureto give a gum which was triturated with diethyl ether/hexane, givingCompound IX.42 (0.43 g). M(NH4)⁺ =298; ¹ H NMR: δ 2.52(2H,m);3.72(2H,t); 4.10-4.30(3H,m); 8.05(1H,s); (mp 118.4-122.0° C.).

EXAMPLE X.1

This Example illustrates two related syntheses ofmercapto-1,2,4-oxadiazoles required as intermediates for preparation ofcompounds of the invention. A general method for synthesis of5-mercapto-1,2,4-oxadiazoles is by cyclisation of an amidoxime and anactivated thiocarbonyl compound such as thiophosgene or1,1-thiocarbonyldiimidazole. Use of the first of these reagents isillustrated by the preparation of 5-mercapto-3-phenyl-1,2,4-oxadiazole.

Benzonitrile (15 g), hydroxylamine hydrochloride (10 g), potassiumcarbonate (10 g), ethanol (150 cm³) and water (15 cm³) were heatedtogether at reflux for 6 hours and then allowed to cool overnight. Thereaction mixture was filtered and the solid residue washed with ethanol.The filtrate and washings were combined and evaporated and the resultantbrown residue partitioned between ethyl acetate and water. The organicphase was separated, washed with brine and dried (MgSO₄). Evaporationgave a brown oil which crystallised on addition of ethyl acetate andhexane to give a grey solid (10.3 g). The solid (4.4 g) was stirred inether (50 cm³) and thiophosgene (0.55 cm³) was added causing a thickwhite precipitate to form. The reaction was heated at reflux for 1 hourand then allowed to cool. A solution of sodium hydroxide in water (50cm³) was then added and the reaction heated for a further 4 hours, thenallowed to cool to leave a yellow biphasic reaction mixture. The organicphase was separated and the aqueous layer was extracted twice withether. The aqueous layer was acidified to pH 1 causing formation of ayellow ppt. The aqueous layer was extracted with ethyl acetate and thecombined ethyl acetate layers were dried (MgsO₄) and evaporated to give5-mercapto-3-phenyl-1,2,4-oxadiazole as an orange-brown solid (0.554 g),which was used without further purification. ¹ H NMR: δ 7.45-7.63(3H,m);7.70-7.90(2H,m).

Use of the alternative reagent 1,1-thiocarbonyldiimidazole, isillustrated by the preparation of5-mercapto-3-methoxymethyl-1,2,4-oxadiazole.

Methoxyacetonitrile (7.1 g), hydroxylamine hydrochloride (7 g),potassium carbonate (13.8 g), ethanol (90 cm³) and water (9 cm³) wereheated together at 50° C. for 9 hours and then allowed to cool. Thereaction mixture was filtered and the white solid residue washed withethyl acetate. The filtrate and washings were combined and evaporatedand the resultant residue dissolved in dichloromethane. Insolublematerial was removed by filtration and the filtrate evaporated to give aviscous oil (9.2 g). The oil was added to toluene (60 cm³) and drydimethylformamide (4 cm³) containing 1,1-thiocarbonyldiimidazole (5.655g) and the mixture was stirred at the ambient temperature for 2 hours.After standing for a further 60 hours the beige solid which had formedwas recovered by filtration (5.2 g obtained) and shown by NMR to be theuncyclised product of reaction between the hydroxy group of theamidoxime and the thiocarbonyl group. A portion of the solid (2 g) wasadded to a suspension of sodium hydride (0.33 g) in drydimethylformamide (30 cm³) (frothing) and the mixture was stirred at theambient temperature for 5 hours and left to stand for 18 hours. Thereaction product was poured into water and the product extracted intoethyl acetate. The combined organic phases were separated dried (MgSO₄)and evaporated under reduced pressure, finally at high vacuum to removetraces of dimethylformamide. The crude5-mercapto-3-methoxymethyl-1,2,4-oxadiazole had ¹ H NMR: δ 3.2(3H,s);4.10(2H,s); 6.92-6.98(1H,br s) and was used without furtherpurification.

EXAMPLE X.2

This Example illustrates a general process for the preparation of 5-(4,4-difluorobut-3-enylthio)-3-substituted-1,2,4-oxadiazoles using thecorresponding 5-mercapto intermediate prepared for example as above.This is illustrated by the following preparation of5-(4,4-difluorobut-3-enylthio)-3-methoxymethyl-1,2,4-oxadiazole,Compound X.26.

To a solution of 5-mercapto-3-methoxymethyl-1,2,4-oxadiazole (2.78 g) inacetone (150 cm³) was added 4-bromo-1,1-difluorobut-1-ene (4.87 g) andpotassium carbonate (3.15 g) and the mixture heated under reflux for 18hours. Gc indicated that reaction was complete. Inorganic solids wereremoved by filtering the reaction mixture through a plug of sorbsil-C30silica, washing-with acetone. The filtrate was evaporated under reducedpressure and the yellow oily residue was chromatographed on sorbsil-C30,eluting with 5% ethyl acetate in hexane, to give Compound X.26 (1.6 g) ¹H NMR: δ 2.47-2.58(2H,m); 3.28-3.35(2H,t); 3.49(3H,s); 4.18-4.36(1H,m);4.54(2H,s); (oil).

The following compounds according to the invention were prepared usingthe above procedure and the appropriate intermediates indicated:

(i) 5-(4,4-difluorobut-3-enylthio)-3-methyl-1,2,4-oxadiazole (CompoundX.32). ¹ H NMR: δ 2.37(3H,s); 2.45-2.55(2H,m); 3.22-3.30(2H,t);4.16-4.35(1H,m); (oil) from 5-mercapto-3-methyl-1,2,4-oxadiazole.

(ii) 5-(4,4-difluorobut-3-enylthio)-3-phenyl-1,2,4-oxadiazole (CompoundX.1). M⁺ =268; ¹ H NMR: δ 2.58(2H,m); 3.35(2H,t); 4.31(1H,m);7.45-7.56(3H,m); 8.07(2H,d); (oil) from5-mercapto-3-phenyl-1,2,4-oxadiazole.

EXAMPLE X.3

This Example illustrates a preparation of5-(4,4-difluorobut-3-enylsulfonyl)-3-methyl-1,2,4-oxadiazole (CompoundX.27) from Compound X.26.

Compound X.26 (0.6 g) was cooled to 0° C. in dichloromethane (50 cm³)and 3-chloroperbenzoic acid (2.19 g, 2.5 equiv.) was added over a periodof five minutes. The mixture was stirred at the ambient temperature for1 hour and stood for 40 hours. The reaction mixture was poured intosaturated aqueous sodium bicarbonate and the product was extracted intodichloroethane. The organic layer was washed with saturated aqueoussodium bicarbonate, water and saturated brine and dried (MgSO₄).Evaporation of solvent under reduced pressure gave a light brown solidwhich was chromatographed on silica, eluting with 10% ethyl acetate inhexane, progressing to 20% ethyl acetate in hexane, to give CompoundX.27 having ¹ H NMR: δ 2.6-2.71(2H,m); 3.51(3H,s); 3.58-3.65(2H,t);4.21-4.37(1H,m); 4.69(2H,s); (oil). This material was found to beunstable and on standing for 60 hours at the ambient temperature hadhydrolysed appreciably.

EXAMPLE XI.1A

This Example illustrates a general procedures for the preparation of5-chloro-3-substituted-1,2,4-thiadiazoles as demonstrated by thefollowing preparation of 5-chloro-3-chloromethyl-1,2,4-thiadiazole fromchloroacetamidine hydrochloride.

A suspension of chloroacetamidine hydrochloride (12.9 g) indichloromethane (100 cm³) was cooled to -5° C. and perchloromethylmercaptan (20.44 g) was added. Sodium hydroxide in water (20 g in 30cm³)was added dropwise (exotherm), maintaining the temperature of thereaction mixture below 5° C. After the addition was complete, thereaction was allowed to warm to the ambient temperature and stirredovernight. The mixture was diluted with water and dichloromethane andthe whole filtered through a pad of celite to remove insoluble material.The organic phase was separated, washed with saturated brine and driedover magnesium sulfate. The solution of product was then filtered andevaporated under reduced pressure to give a brown oil (9.72 g) which wasused without further purification. M⁺ =168; ¹ H NMR: δ 4.75(s).

The following intermediate compounds were prepared according to theprocedure of Example XI.1A. The starting materials were known compounds.

(i) 5-chloro-3-trifluoromethyl-1,2,4-thiadiazole. M⁺ =188 (bp 50° C. at12 mmHg).

(ii) 5-chloro-3-methylmercapto-1,2,4-thiadiazole. M⁺ =166.

(iii) 5-chloro-3-methoxy-1,2,4-thiadiazole. M⁺ =150.

(iv) 5-chloro-3-(2-pyrazinyl)-1,2,4-thiadiazole. M⁺ =198.

A related procedure was used to prepare Compound XI.102 of theinvention, as follows.

Preparation of 5-chloro3-(4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole

A suspension of 4,4-difluorobut-3-enylisothiouronium hydrobromide (8.68g) in water (200 cm³) containing sodium lauryl sulfate (0.1 g,catalytic) and perchloromethyl mercaptan (7.17 g) was cooled to 0° C.and sodium hydroxide in water (5.6 g in 200 cm³) was added dropwise,maintaining the temperate of the reaction mixture below 5° C. After theaddition was complete, the reaction was allowed to warm to the ambienttemperature and stirred overnight. The mixture was extracted twice withethyl actetate, the organic phase was separated, washed with saturatedbrine and dried (MgSO₄). The solution of product was then filtered andevaporated under reduced pressure to give a brown oil (8.2 g) which waschromatographed on silica gel (Sorbsil C30) using 3% ethyl acetate inhexane as eluant to give Compound XI.102 (2.82 g). M⁺ =242; ¹ H NMR: δ2.4-2.6(2H,m); 3.2-3.3(3H,t); 4.2-4.4(1H,m); (oil).

EXAMPLE XI.1B

A general procedure for the preparation of 5-(4-methylphenyl)-sulfonyl!-3-substituted-1,2,4-thiadiazoles isillustrated by the following two-step preparation of 3-methoxymethyl-5-(4-methylphenyl)-sulfonyl!-1,2,4-thiadiazole from methoxyacetamide.

Step 1: Preparation of 5-methoxyethyl-1,3,4-oxathiazol-2-one

Chlorocarbonylsulfenyl chloride.(7.35 g) was added to a suspension ofmethoxyacetamide (5 g) in toluene (30 cm³). The reaction mixture wasstirred and heated at 90-100° C. for 5 hours, then cooled. The solventwas removed by evaporation under reduced pressure to give a brown gum(6.6 g). M⁺ =147; ¹ H NMR (DMSO-d₆): δ 3.30(3H,s); 4.30(2H,s) which wasused in the next step without further purification.

Step 2: Preparation of 3-methoxymethyl-5-(4-methylphenyl)-sulfonyl!-1,2,4-thiadiazole

4-Methylbenzenesulfonyl cyanide (16.26 g) was added to an emulsion of5-methoxymethyl-1,3,4-oxathiazol-2-one (6.6 g) in dodecane (60 cm³). Thereaction mixture was stirred and heated at 150° C. for 18 hours, thencooled. Water was added and the product extracted into ethyl acetate.The combined organic phases were dried (MgSO₄) and ethyl acetate wasremoved by evaporation under reduced pressure. The residue separatedinto a brown liquid and a clear dodecane layer which was removed anddiscarded. Chromatography of the brown liquid on silica gel (SorbsilC30) using 3:7 ethyl acetate:hexane as eluant give a pale orange oilwhich solidified on standing (6.94 g). M⁺ =284; ¹ H NMR: δ 2.40(3H,s);3.45(3H,s); 4.7(2H,s); 7.4(2H,d); 8.0(2H,d); (mp 43.4-45-4° C.).

The following intermediate compounds were prepared according to thetwo-step procedure of Example XI.1B. The starting materials were knowncompounds.

(i) 3-ethyl-5- (4-methylphenyl)-sulfonyl!-1,2,4-thiadiazole. M⁺ =268; ¹H NMR: δ 1.3-1.4(3H,t); 2.45(3H,s); 2.95-3.05(2.H,q); 7.4(2H,m);8.0(2H,m) from propionamide.

(ii) 3-(E-prop-1-enyl)-5- (4-methylphenyl)-sulfonyl!-1,2,4-thiadiazole.M⁺ =280; ¹ H NMR: δ 1.95(3H,dd); 2.45(3H,s); 6.5-6.6(1H,m);7.0-7.1(1H,m); 7.4(2H,m); 8.0(2H,m) from crotonamide.

EXAMPLE XI.2

This Example illustrates a process for the preparation of5-(4,4-difluorobut-3-enylthio)-3-substituted-1,2,4-thiadiazoles usingeither the corresponding 5-chloro- or 5-(4-methylphenyl)-sulfonyl!-1,2,4-thiadiazole intermediate prepared asabove The general procedure is illustrated by the following preparationof 5-(4,4-difluorobut-3-enylthio)-3-methoxymethyl-1,2,4-thiadiazole(Compound XI.34).

Sodium hydroxide in water (0.848 g in 10 cm³) was added to4,4-difluorobut-3-enylisothiouronium hydrobromide (1.75 g) and themixture stirred at ambient temperature for 20 minutes. A solution of3-methoxymethyl-5- (4methylphenyl)-sulfonyl!-1,2,4-thiadiazole (2.01 g)in dichloromethane (10 cm³) and tetrabutylammonium bromide (0.1 g,catalyst) were added and the mixture was stirred for 20 minutes. Tlcshowed hat the product had formed. The mixture was diluted with moredichloromethane (10 cm³) and the organic phase was separated, washedwith saturated brine dried (MgSO₄), filtered and evaporated underreduced pressure to give an orange-yellow liquid. Chromatography of thecrude product on silica gel (Sorbsil C30) using 1:4 ethyl acetate:hexaneas eluant give Compound XI.34 (1.67 g). M³⁰ =252; ¹ H NMR: δ2.45-2.55(2H,m); 3.25-3.35(2H,t); 3.5(3H,s); 4.15-4.35(1H,m);4.65(2H,s); (oil).

The following compounds according to the invention were prepared usingthe above procedure but with the appropriate intermediates.

(i) 5-(4,4-difluorobut-3-enylthio)-3-trifluoromethyl-1,2,4-thiadiazole(Compound XI.9). M⁺ =276; ¹ H NMR: δ 2.5-2.6(2H,m); 3.3-3.4(2H,t);4.2-4.4(1H,m); (oil).

(ii) 5-(4,4-difluorobut-3-enylthio)-3-(E-prop-1-enyl)-1,2,4-thiadiazole(Compound XI.11). M⁺ =248; ¹ H NMR: δ 1.95(3H,dd); 2.5-2.6(2H,m);3.3(2H,t); 4.2-4.4(1H,m); 6.45-6.55(1H,m); 6.9-7.1(1H,m); (oil).

(iii) 3-ethyl-5-(4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole (CompoundXI.23). M⁺ =236; ¹ H NMR: δ 1.3-1.4(3H,t); 2.45-2.55(2H,m);2.9-3.0(2H,q); 3.3(2H,t); 4.2-4.4(1H,m); (oil).

(iv) 3-chloromethyl-5-(4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole(Compound XI.25). M⁺ =256; ¹ H NMR: δ 2.45-2.55(2H,m); 3.35(2H,t);4.2-4.35(1H,m); 4.7(2H,s); (oil). Two further products were produced inthis reaction, which were separated during the chromatography andcharacterised. These were3-(4,4-difluorobut-3-enylthiomethyl)-5-(4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole(Compound XI.38). M⁺ =344; ¹ H NMR: δ 2.25-2.35(2H,m); 2.45-2.55(2H,m);2.65(2H,t); 3.3(2H,t); 3.9(2H,s); 4.15-4.35(2H,m); (oil) and5-chloro-3-(4,4-difluorobut-3-enylthiomethyl)-1,2,4-thiadiazole. M⁺=256; ¹ H NMR: δ 2.2-2.3(2H,m); 2.65(2H,t); 3.9(2H,s); 4.1-4.3(1H,m);(oil)

(v) 5-(4,4-difluorobut-3-enylthio)-3-methoxy-1,2,4-thiadiazole (CompoundXI.87). M⁺ =238; ¹ H NMR: δ 2.4-2.55(2H,m); 3.3(2H,t); 4.1(3H,s);4.2-4.35(1H,m) (oil)

(vi) 3,5-bis-(4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole (CompoundXI.109). M⁺ =330; ¹ H NMR: δ 2.45-2.6(4H,m); 3.2-3.35(4H,m);4.2-4.4(2H,m); (oil) from Compound XI.102.

(vii) 5-(4,4-difluorobut-3-enylthio)3-(2-pyraznyl)-1,2,4-thiadiazole(Compound XI.125). M⁺ =286; ¹ H NMR: δ 2.55-2.65(2H,m); 3.35-3.45(2H,t);4.25-4.40(1H,m);8.65(1H,d); 8.75(1H,dd); 9.55(1H,d); (oil)

EXAMPLE XI.3

This Example illustrates the preparation of3-butoxymethyl-5-4,4-difluorobut-3-enylthio)-1,2,4-thiadiazole (CompoundXI.30).

Potassium carbonate (0.444 g) and n-butanol (0.397 g) were added to asolution of Compound XI.25 (0.275 g) in dimethylformamide (2 cm³) andthe mixture was stirred at ambient temperature for 18 hours. Tlcindicated that Compound XI.25 was still present in the mixture, sosodium hydride (0.1 g) and n-butanol (0.4 g) were added and stirringcontinued for a further 24 hours. Water was added and the product wasextracted into diethyl ether. The organic phase was dried (MgSO₄),filtered and evaporated under reduced pressure to give an oil (0.442 g)which was purified by chromatography on silica gel (Sorbsil C30) using10% ethyl acetate in hexane as eluant to give Compound XI.30 (0.131 g).M⁺ =294; ¹ H NMR: δ 0.95-1.0(3H,t); 1.4-1.55(2H,m); 1.75-1.9(2H,m);2.25-2.45(2H,m); 2.6-2.7(2H,t); 3.75(2H,s); 4.15-4.3(1H,m);4.4-4.5(2H,t); (oil).

The following compound according to the invention was prepared using theabove procedure, with n-propanol in place of n-butanol.

(i) 5-(4,4-difluorobut-3-enylthio)-3-propoxymethyl-1,2,4-thiadiazole(Compound XI.31). M⁺ =280; ¹ H NMR: δ 1.0-1.1(3H,t); 1.8-1.95(2H,m);2.25-2.35(2H,m); 2.6-2.7(2H,t); 3.75(2H,s); 4.15-4.4(1H,m);4.4-4.45(2H,t); (oil).

EXAMPLE XI.4

This Example illustrates a two step process for the preparation of5-(4,4-difluorobut-3-enylthio)-3-methyl-1,2,4-thiadiazole (CompoundXI.40).

Step 1: Preparation of 3-methyl-1,2,4-thiadiazole-5(4H)-thione

To a solution of acetamidine (5 g) in methanol (100 cm³) was addedcarbon disulfide (4 g), sulfur (1.7 g), and sodium methoxide (5.7 g) andthe mixture was heated under reflux for 6 hours. The mixture was cooled,filtered through hi-flo filter aid to remove excess sulfur and thefiltrate was partitioned between water and ethyl acetate. The ethylacetate was evaporated to give a brown solid and on acidification of theaqueous layer a red solid was formed and filtered off. Both the solidsobtained from the filtrate appeared to be a mixture of3-methyl-1,2,4-thiadiazole-5(4H)-thione and sulfur. These two solidswere combined and used in the next step.

Step 2: Preparation of Compound XI.40

To a solution of 3-methyl-1,2,4-thiadiazole-5(4H)-thione (1.2 g) inacetone (100 cm³) was added 4,4-difluorobut-3-enyl4-methylbenzenesulfonate (2.4 g) and potassium carbonate (1.2 g) and themixture was refluxed for 4 hours after which tlc indicated completeconsumption of starting material. The reaction was poured into ethylacetate and water and the layers separated. The aqueous layer wasextracted with ethyl acetate and the combined organic layers were dried(MgSO₄). The solution of product was then filtered and evaporated underreduced pressure to give a brown oil which was purified by flashchromatography (silica, 7% ethyl acetate in hexane) to give5-(4,4-difluorobut-3-enylthio)-3-methyl-1,2,4-thiadiazole as a brown oil(0.645 g). M⁺ =222; ¹ H NMR: δ 2.56(2H, br q); 2.63 (3H,s); 3.30(2H,t);4.30(1H,m).

The following compound according to the invention was prepared using theabove procedure but with 3-phenyl-1,2,4-thiadiazole-5(4H)-thione asstarting material.

(i) 5-(4,4-difluorobut-3-enylthio)-3-phenyl-1,2,4-thiadiazole (CompoundXI.5). ¹ H NMR: δ 2.53(2H,q); 3.30(2H,t); 4.24(1H,m); 7.38(3H,m);8.2(2H,m).

EXAMPLE XI.5

This Example illustrates the preparation of3-(4,4-difluorobut-3-enylthio)-5-methoxy-1,2,4-thiadiazole (CompoundXI.108).

Sodium hydroxide (0.182 g) was added to a solution of Compound XI.102 (1g) in methanol (5 cm³) and the mixture stirred at the ambienttemperature for 45 minutes, when tlc indicated consumption of startingmaterial. Water and diethyl ether were added to the mixture and theproduct was extracted into diethyl ether. The organic phase was dried(MgSO₄), filtered and evaporated under reduced pressure to give a yellowoil (0.9 g). Purification by flash chromatography (silica, 5% ethylacetate in hexane) gave Compound XI.108 (0.78 g). M⁺ =238; ¹ H NMR: δ2.4-2.5(2H,m); 3.2(2H,t); 4.15(3H,s); 4.2-4.35(1H,m); (oil).

EXAMPLE XI.6

This Example illustrates the preparation of5-(4,4-difluorobut-3-enylthio)-3-methylthio-1,2,4-thiadiazole (CompoundXI.110).

Sodium sulfide nonahydrate (0.555 g) was added to5-chloro-3-methylthio-1,2,4-thiadiazole (1.5 g) in ethanol (10 cm³) andthe mixture stirred and heated under reflux for 18 hours. The reactionmixture was cooled and solvent removed by evaporation under reducedpressure to give a yellow solid (1.76 g) which was dissolved in actetone(30cm³). Potassium carbonate (2.22 g) and 4-bromo-1,1-difluorobut-1-ene(1.83 g) were added and the mixture stirred and heated under reflux for18 hours. The reaction mixture was cooled, filtered through hi-flofilter aid to remove inorganic material, washing with ethyl acetate, andsolvent removed by evaporation under reduced pressure to give a browngum which was purified by chromatography on silica gel (Sorbsil C30)using 5% ethyl acetate in hexane as eluant to give Compound XI.110(0.392 g). M⁺ =254; ¹ H NMR: δ 2.45-2.55(2H,m); 2.65(3H,s);3.25-3.35(2H,t); 4.2-4.4(1H,m); (oil).

EXAMPLE XI.7

This Example illustrates the preparation of5-(4,4-difluorobut-3-enylthio)-3-(3-nitrophenyl)-1,2,4-thiadiazole(Compound XI.127).

Hydrogen sulfide gas was bubbled for 40 minutes through a stirredmixture of potassium methoxide (2.2 g) and absolute ethanol (25 cm³),cooled at ˜-10° C. The flask was removed from the cooling bath,5-chloro-3-(3-nitrophenyl)-1,2,4-thiadiazole (3 g) was added, and themixture was heated under reflux for 1 hour. The reaction was cooled andpoured into ether and the resulting precipitate was filtered off. Thefiltrate, containing 5-mercapto-3-(3-nitrophenyl)-1,2,4-thiadiazole, wasthen placed in a flask and 4,4-difluorobut-3-enyl4-methylbenzenesulfonate (1.5 g) and ˜1 g of potassium carbonate wereadded and the mixture was heated under reflux for 3 hours after which gcindicated virtually complete consumption of tosylate. The reaction waspoured into ethyl acetate and water and the layers separate The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere dried (MgSO₄). Evaporation under reduced pressure gave a brownliquid which was purified by flash chromatography (silica; eluant 5%ethyl acetate in hexane) to give Compound XI.127 (0.901 g). M⁺ =329; ¹ HNMR: δ 2.60(2H,broad q) 3.44(2H,t); 4.34(1H,m); 7.65(1H,t); 8.32(1H,dd);8.6(1H,d); 9.1(1H,d) (oil).

EXAMPLE XI.8

This Example illustrates a method suitable for the preparation ofcompounds according to the invention in which the sulfur atom of the4,4-difluorobut-3-enylthio substituent of the corresponding unoxidisedcompound (prepared according to the procedures of the precedingExamples) is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).

Preparation of Compounds XI.35 and XI.36 from Compound XI.1.34.

Compound XI.34 (0.85 g) was stirred at ambient temperature indichloromethane (10 cm³) and 3-chloro perbenzoic acid (0.814 g, 1.4equiv.) was added. After three and a half hours, tlc indicatedconsumption of starting material, with the formation of two products.The reaction was quenched by the addition of a saturated aqueoussolution of sodium bicarbonate and the products were extracted intodichloromethane. The organic phase was separated, washed with saturatedbrine and dried over magnesium sulfate. After filtration andconcentration by evaporation under reduced pressure, there was obtaineda white solid (1.2 g) which was purified by chromatography on silica gelusing 3:7 ethyl acetate:hexane as eluant to give first 5-(4,4-difluorobut-3-enyl)sulfonyl!-3-methoxymethyl-1,2,4-thiadiazole(Compound XI.36) (0.298 g). M⁺ =284; ¹ H NMR: δ 2.55-2.65(2H,m);3.55(3H,s); 3.5-3.6(2H,t); 4.24.35(1H,m); 4.80(2H,s); (oil). Furtherelution gave 5-(4,4-difluorobut-3-enyl)sulfinyl!-3-methoxymethyl-1,2,4thiadiazole(Compound XI.35) (0.402 g). M⁺ =268; ¹ H NMR: δ 2.3-2.75(2H,m);3.15-3.4(2H,m); 3.55(3H,s); 4.15-4.35(1H,m); 4.75(2H,s); (oil).

The following compound according to the invention was prepared by theabove procedure, using two equivalents of oxidant.

(i) 5- (4,4-difluorobut-3-enyl)sulfonyl!-3-ethyl-1,2,4-thiadiazole(Compound XI.24) M⁺ =268; ¹ H NMR: δ 1.4-1.5(3H,t); 2.55-2.65(2H,m);3.05-3.15(2H,q); 3.5-3.55(2H,t); 4.2-4.4(1H,m); (oil).

EXAMPLE XII.1

Methods for synthesis of the mercapto 1,3,4-oxadiazoles used asintermediates in preparing compounds according to the invention are wellknown in the art. Two representative methods are illustrated below.

Method A Preparation of 2-mercapto-5-methyl-1,3,4-oxadiazole.

To a solution of acetic hydrazide (5 g) in ethanol (10 cm³) was addedcarbon disulfide (7.7 g) followed by a solution of potassium hydroxidein ethanol (5.7 g in 20 cm³) which caused a white precipitate to form.The reaction was then stirred at ambient temperature for 2 hours andleft to stand overnight. The reaction was filtered to give a white solid(11 g). This salt (5 g) was taken up in pyridine (10 cm³) and themixture heated under reflux for a total of 14 hours. After cooling, thereaction was acidified and extra twice with diethyl ether. The etherlayer was dried over magnesium sulfate, filtered and evaporated underreduced pressure to give an orange solid. This was recrystallised fromethyl acetate to give 2-mercapto-5-methyl-1,3,4oxadiazole (0.655 g). M⁺=116; ¹ H NMR: δ 2.43(3H,s); 10.9(1H,br s).

Method B Preparation of5-(4-methoxybenzyl)-1,3,4-oxadiazole-2(3H)-thione.

Step 1: Preparation of (4-methoxyphenyl)acetic acid hydrazide.

Hydrazine hydrate (4.7 cm³) was added dropwise to ethyl(4-methoxyphenyl)acetate (3.73 g) and then methanol (20 cm³) was addedto form a homogeneous reaction mixture. This mixture was stirred for 18hours at ambient temperature during which time a white precipitateformed. The precipitate was isolated by filtration and washed withmethanol and water, then air-dried to give (4-methoxyphenyl)acetic acidhydrazide (2 g). M⁺ =180; ¹ H NMR: δ 3.50(2H,s); 3.80(3H,s); 3.85(2H,brs); 6.70(1H,br s); 6.90(2H,d); 7.20(2H,d); (solid).

The following intermediate compounds were made by the above methods:

(i) 2-methylpropanoic acid hydrazide. M.sup. +=102; (solid).

(ii) cyclopropylacetic acid hydrazide. M⁺ =100; (solid).

(iii) butanoic acid hydrazide. ¹ H NMR: δ 0.95(3H,t); 1.60-1.75(2H,m);2.15(2H,t); 3.90(2H,br s); 6.95(1H,br s); (solid).

(iv) propanoic acid hydrazide. M⁺ =88; (solid).

(v) pentanoic acid hydrazide. ¹ H NMR: δ 0.90(3H,t); 1.30-1.40(2H,m);1.60-1.70(2H,m); 2.20(2H,t); 3.90(2H,br s); 6.80(1H,br s); (solid).

(vi) hexanoic acid hydrazide. ¹ H NMR: δ 0.90(3H,t); 1.20-1.35(4H,m);1.601.70(2H,m); 2.15(2H,t); 3.90(2H,br s); 6.70(1H,br s); (solid).

(vii) (4-nitrophenyl)acetic acid hydrazide. ¹ H NMR: δ (DMSO-d₆)3.50(2H,s); 7.50(2H,d); 8.10(2H,d); (solid).

(viii) (2,6-difluorophenyl)acetic acid hydrazide. M⁺ =186; ¹ H NMR: δ3.60(2H,s); 6.90-7.00(2H,m); 7.20-7.30(1H,m); (solid).

(ix) 2-methylbenzoic acid hydrazide. M⁺ =150; ¹ H NMR: δ 2.45(3H,s);4.10(2H,br s); 7.00(1H,br s); 7.20-7.40(4H,m); (solid).

Step 2: Preparation of 5-(4-methoxybenzyl)-1,3,4oxadiazole-2(3-thione.

A solution of potassium hydroxide (0.7 g) in water (2 cm³) was added toa stirred solution of (4-methoxyphenyl)acetic acid hydrazide (1.99 g) inethanol (30 cm³). carbon disulfide (0.7 cm³) was added and the reactionwas heated to reflux for 6 hours and then left to cool. The reactionmixture was evaporated to dryness under reduced pressure and the solidresidue dissolved in water. The pH was adjusted to 1 with concentratedhydrochloric acid, resulting in formation of a white precipitate. Theprecipitate was isolated by filtration; washed with water and ether andair dried to give 5-(4-methoxybenzyl)-1,3,4-oxadiazole-2(3H)-thione(1.96 g). M⁺ =222; ¹ H NMR: δ 3.80(3H,s); 3.95(2H,s); 6.90(2H,d);7.20(2H,d); (solid).

The following compounds were prepared by the above method, using theappropriate intermediate (either known compounds or as prepared in Step1):

(i) 1,3,4-thiadiazole-2(3H)-thione-5-carboxamide. M⁺ =145; (solid).

(ii) 5-thienyl-1,3,4-thiadiazole-2(3H)-thione. M⁺⁼¹⁸⁴ ; (solid).

(iii) 5-isopropyl-1,3,4-thiadiazole-2(3H)-thione. M⁺ =144; (gum).

(iv) 5-cyclopropyl-1,3,4-thiadiazole-2(3H)-thione. M⁺ =142; (gum).

(v) 5-propyl-1,3,4-thiadiazole-2(3H)-thione. M⁺ =144; (oil).

(vi) 5-ethyl-1,3,4-thiadiazole-2(3H)-thione. M⁺ =130; (oil).

(vii) 5-(4-pyridyl)-1,3,4-thiadiazole-2(3H)-thione. M⁺ =179; ¹ H NMR: δ7.75(2H,d); 8.75(2H,d); (solid).

(viii) 5-butyl-1,3,4-thiadiazole-2(3H)-thione. ¹ H NMR: δ 0.95(3H,t);1.35-1.50(2H,m); 1.65-1.75(2H,m); 2.70(2H,t); 2.90(1H,br s); (oil).

(ix) 5-pentyl-1,3,4-thiadiazole-2(3H)-thione. ¹ H NMR: δ 0.90(3H,t);1.25-1.45(4H,m); 1.75(2H,m); 2.70(2H,m); (oil).

(x) 5-(4-nitrobenzyl)-1,3,4-thiadiazole-2(3H)-thione. M⁺ =237; ¹ H NMR:δ 4.20(2H,s); 7.50(2H,d); 8.25(2H,d); (solid).

(xi) 5-(2,6,-difluorobenzyl)-1,3,4-thiadiazole-2(3H)-thione. ¹ H NMR: δ4.10(2H,s); 6.90-7.00(2H,m); 7.25-7.40(1H,m); (solid).

(xii) 5-(4-methoxyphenyl)-1,3,4-thiadiazole-2(3H)-thione. ¹ H NMR: δ3.80(3H,s); 7.10(2H,d); 7.75(2H,d); (solid).

(xiii) 5-(2-methylphenyl)-1,3,4-thiadiazole-2(3H)-thione. ¹ H NMR: δ(DMSO-d₆) 2.50(3H,s); 7.30-7.40(2H,m); 7.40-7.50(1H,m); 7.55(1H,br d);(solid).

(xiv) 5-(2-methoxyphenyl)-1,3,4-thiadiazole-2(3H)-thione. M⁺ =208;(solid).

(xv) 5-(4-nitrophenyl)-1,3,4-thiadiazole-2(3H)-thione. M⁺ =223; ¹ H NMR:δ 8.05(2H,d); 8.30(2H,d); (solid).

(xvi) 5-benzyl-1,3,4-oxadiazole-2(3H)-thione. ¹ H NMR: δ 4.00(2H,s);7.25-7.40(5H,m); (solid).

EXAMPLE XII.2

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-5-phenyl-1,3,4-oxadiazole (CompoundXII.3).

To a solution of 2-mercapto-5-phenyl-1,3,4-oxadiazole (0.499 g) inacetone (15 cm³) was added potassium carbonate (0.387 g) and4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (0.7 g) and the mixturewas heated under reflux for 1.5 hours after which time all startingmaterial had been consumed. The reaction was poured into diethyl etherand water and the layers separated. The aqueous layer was extracted withether and the combined organic layers were washed with water and dried(MgSO₄). Evaporation of solvent under reduced pressure gave a paleyellow liquid which was purified by flash chromatography to giveCompound XII.3 as a colourless oil that solidified on standing (0.293g). M⁺ =268; ¹ H NMR: δ 2.58(2H,m); 3.32(2H,t); 4.31(1H,m);7.45-7.57(3H,m); 8.01(2H,d); (mp 38-40° C.).

The following compounds according to the invention were prepared fromthe appropriate intermediate (either known compounds or prepared as inExample XII.1) using the above method but with4-bromo-1,1-difluorobut-1-ene as alkylating agent instead of4,4-difluorobut-3-enyl 4-methyl-benzenesulfonate.

(i) 5-cyclopropyl-2-(4,4-difluorobut-3-enylthio 1,3,4-oxadiazole(Compound XII.1). ¹ H NMR: δ 1.10-1.15(4H,m); 2.10-2.20(1H,m);2.45-2.55(2H,m); 3.20(2H,t); 4.30(1H,m); (oil).

(ii) 2-(4,4-difluorobut-3-enylthio)-5-isopropyl-1,3,4-oxadiazole(Compound XII.8). M⁺ =234; ¹ H NMR: δ 1.19(6H,d); 2.50-2.60(2H,m);3.15(1H,septet); 3.30(2H,t); 4.30(1H,m); (oil).

(iii)5-(2,6-difluorobenzyl)-2-(4,4-difluorobut-3-enylthio)-1,3,4-oxadiazole(Compound XII.11). ¹ H NMR: δ 2.45-2.55(2H,m); 3.25(2H,t); 4.20(2H,s);4.25(1H,m); 6.90-7.00(2H,m); 7.25-7.35(1H,m); (oil).

(iv) 2-(4,4-difluorobut-3-enylthio)-5-(4-nitrobenzyl)-1,3,4-oxadiazole(Compound XII.12). ¹ H NMR: δ 2.50-2.60(2H,m); 3.30(2H,t); 4.20(1H,m);4.30(2H,s); 7.50(2H,d); 8.20(2H,d); (oil).

(v) 2-(4,4-difluorobut-3-enylthio)-5-isobutyl-1,3,4-oxadiazole (CompoundXII.23). ¹ H NMR: δ 1.00(6H,d); 2.10-2.20(1H,m); 2.50-2.60(2H,m);2.70(2H,d); 3.25(2H,t); 4.30(1H,m); (oil).

(vi) 2-(4,4-difluorobut-3-enylthio)-5-pentyl-1,3,4-oxadiazole (CompoundXII.25). ¹ H NMR: δ 0.90(3H,t); 1.30-1.40(4H,m); 1.70-1.80(2H,m);2.50-2.55(2H,m); 2.80(2H,t); 3.25(2H,t); 4.30(1H,m); (oil).

(vii) 5-butyl-2-(4,4-difluorobut-3-enylthio)-1,3,4-oxadiazole (CompoundXII.28). ¹ H NMR: δ 0.95(3H,t); 1.35-1.50(2H,m); 1.70-1.80(2H,m);2.50-2.60(2H,m); 2.80(2H,t); 3.25(2H,t); 4.30(1H,m); (oil).

(viii) 2-(4,4-difluorobut-3-enylthio)-5-propyl-1,3,4-oxadiazole(Compound XII.31). ¹ H NMR: δ 1.00(3H,t); 1.75-1.90(2H,m);2.50-2.60(2H,m); 2.80(2H,t); 3.25(2H,t); 4.30(1H,m); (oil).

(ix) 2-(4,4-difluorobut-3-enylthio)-5-ethyl-1,3,4-oxadiazole (CompoundXII.35). ¹ H NMR: δ 1.40(3H,t); 2.50-2.60(2H,m); 2.85(2H,t); 3.25(2H,t);4.30(1H,m); (oil).

(x) 2-(4,4-difluorobut-3-enylthio)-5-methyl-1,3,4-oxadiazole (CompoundXII.49). M⁺ =206; ¹ H NMR: δ 2.51(2H,m); 2.73(3H,s); 3.27(2H,t);4.25(1H,m); (oil).

(xi) 2-(4,4-difluorobut-3-enylthio)-1,3,4-oxadiazole-5-carboxamide(Compound XII.55). M⁺ =235; ¹ H NMR: δ 2.50-2.60(2H,m); 3.35(2H,t);4.30(1H,m); (mp 113° C.).

(xii) 2-(4,4-difluorobut-3-enylthio)-5-(2-methylphenyl)-1,3,4-oxadiazole(Compound XII.128). ¹ H NMR: δ 2.55-2.65(2H,m); 2.70(3H,s); 3.35(2H,t);4.30(1H,m); 7.30-7.45(3H,m); 7.90(1H,d); (oil).

(xiii) 2-(4,4-difluorobut-3-enylthio)-5-(2-furyl)-1,3,4-oxadiazole(Compound XII.131). M⁺ =258; ¹ H NMR: δ 2.50-2.60(2H,m); 3.35(2H,t);4.30(1H,m); 6.60(1H,m); 7.10(1H,d); 7.60(1H,d); (oil).

(xiv) 2-(4,4difluorobut-3-enylthio)-5-(2-methoxyphenyl)-1,3,4-oxadiazole(Compound XII.132). ¹ H NMR: δ 2.50-2.60(2H,m); 3.30(2H,t); 3.95(3H,s);4.30(1H,m); 7.10(2H,m); 7.50(1H,dt); 7.90(1H,dd); (mp 35-37° C.).

(xv) 2-(4,4-difluorobut-3-enylthio)-5-(2-thienyl)-1,3,4-oxadiazole(Compound XII.133). M⁺ =274; ¹ H NMR: δ 2.50-2.60(2H,m); 3.30(2H,t);4.30(1H,m); 7.10-7.20(1H,m); 7.55(1H,d); 7.70(1H,d); (oil).

(xvi) 2-(4,4-difluorobut-3-enylthio)-5-(3-furyl)-1,3,4-oxadiazole(Compound XII.134). ¹ H NMR: δ 2.50-2.60(2H,m); 3.30(2H,t); 4.30(1H,m);6.90(1H,m); 7.50-7.55(1H,m); 8.05(1H,br s); (oil).

(xvii)2-(4,4-difluorobut-3-enylthio)-5-(4-methoxyphenyl)-1,3,4-oxadiazole(Compound XII.144). ¹ H NMR: δ 2.50-2.60(2H,m); 3.30(2H,t); 3.90(3H,s);4.30(1H,m); 7.00(2H,d); 8.00(2H,d); (oil).

(xviii) 2-(4,4-difluorobut-3-enylthio)-5-(4-pyridyl)-1,3,4-oxadiazole(Compound XII.148). M⁺ =269; ¹ H NMR: δ 2.50-2.65(2H,m); 3.40(2H,t);4.30(1H,m); 7.90(2H,d); 8.80(2H,d); (oil).

EXAMPLE XII.3

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylsulfinyl)-5-phenyl-1,3,4oxadiazole (CompoundXII.4).

To a solution of Compound XII.3 (1 g) in dry dichloromethane stirring at0° C. was added 3-chloroperbenzoic acid (1.3 g of a 50% by weight solid,1 equivalent). The reaction was allowed to warm to ambient temperature,stirred for 3 hours and left overnight. Tlc indicated completeconsumption of starting material. The reaction mixture was filtered andthe filtrate partitioned between dichloromethane and sodium bicarbonatesolution. The aqueous layer was extracted with dichloromethane and thecombined organic phases were dried over magnesium sulfate. Evaporationof solvent under reduced pressure gave a yellow oil which was purifiedby flash chromatography on silica gel, eluting with 25% ethyl acetate inhexane to give Compound XII.4 (0.474 g). N⁺ =284; ¹ H NMR: δ 2.67(2H,m);3.52(2H,m); 4.32(1H,m); 7.50(3H,m); 8.12(2H,d); (oil).

The following compounds according to the invention were prepared fromthe appropriate thioether using the above method

(i)2-(4,4-difluorobut-3-enylsulfinyl)-5-(4-methoxybenzyl)-1,3,4-oxadiazole(Compound XII.14). ¹ HNMR: δ 2.45-2.70(2H,m); 3.30-3.50(2H,m);3.80(3H,s); 4.25(1H,m); 4.25(2H,s); 6.90(2H,d); 7.25(2H,d); (oil).

(ii) 2-(4,4-difluorobut-3-enylsulfinyl)-5-pentyl-1,3,4-oxadiazole(Compound XII.26). ¹ H NMR: δ 0.95(3H,t); 1.30-1.40(4H,m);1.80-1.90(2H,m); 2.50-2.75(2H,m); 2.95(2.95H,t); 3.35-3.55(2H,m);4.30(1H,m); (oil).

(iii) 5-butyl-2-(4,4-difluorobut-3-enylsulfinyl)-1,3,4-oxadiazole(Compound XII.29). ¹ H NMR: δ 1.00(3H,t); 1.40-1.50(2H,m);1.80-1.90(2H,m); 2.50-2.75(2H,m); 3.00(2H,t); 3.35-3.55(2H,m);4.30(1H,m); (oil).

(iv) 2-(4,4-difluorobut-3-enylsulfinyl)-5-propyl-1,3,4-oxadiazole(Compound XII.32). ¹ H NMR: δ 1.05(3H,t); 1.80-1.95(2H,m);2.50-2.75(2H,m); 2.95(2H,t); 3.35-3.55(2H,m); 4.30(1H,m); (oil).

(v)2-(4,4-difluorobut-3-enylsulfinyl)-5-(2-methylphenyl)-1,3,4-oxadiazole(Compound XII.129). ¹ H NMR: δ 2.55-2.80(2H,m); 2.70(3H,s);3.40-3.60(2H,m); 4.30(1H,m) 7.30-7.40(1H,m); 7.45-7.50(1H,m);8.00(1H,d); (oil).

(vi)2-(4,4-difluorobut-3-enylsulfinyl)-5-(4-nitrophenyl)-1,3,4-oxadiazole(Compound XII.142). ¹ H NMR: δ 2.55-2.80(2H,m); 3.45-3.70(2H,m);4.35(1H,m); 8.35(2H,d); 8.45(2H,d); (oil).

(vii)2-(4,4-difluorobut-3-enylsulfinyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole(Compound XII.145). ¹ H NMR: δ 2.50-2.80(2H,m); 3.40-3.60(2H,m);3.90(3H,s); 4.30(1H,m); 7.05(2H,d); 8.05(2H,d); (oil).

The following compounds according to the invention were prepared fromthe appropriate thioether using the general method described above butwith 2 equivalents of 3-chloroperbenzoic acid as oxidant.

(viii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-phenyl-1,3,4-oxadiazole(Compound XII.5). M⁺ =300; ¹ H NMR: δ 2.71(2H,m); 3.67(2H,m);4.33(1H,m); 7.52-7.70(3H,m); 8.25(2H,d); (mp 104-106° C.).

(ix) 2-(4,4-difluorobut-3-enylsulfonyl)-5-isopropyl-1,3,4-oxadiazole(Compound XII.9). ¹ H NMR: δ 1.50(6H,d); 2.60-2.70(2H,m);3.20-3.40(1H,m); 3.60(2H,t); 4.30(1H,m); (gum).

(x) 2-(4,4-difluorobut-3-enylsulfonyl)-5(4-nitrobenzyl)-1,3,4-oxadiazole(Compound XII.13). ¹ H NMR: δ 2.60-2.70(2H,m); 3.60(2H,t); 4.30(1H,m);4.40(2H,s); 7.55(2H,d); 8.25(2H,d); (oil).

(xi)2-(4,4-difluorobut-3-enylsulfonyl)-5-(4-methoxybenzyl)-1,3,4-oxadiazole(Compound XII. 15). ¹ H NMR: δ 2.60-2.70(2H,m); 3.65(2H,t); 3.80(3H,s);4.20(1H,m); 4.25(2H,s); 6.90(2H,d); 7.25(2H,d); (mp 60-63° C.).

(xii) 5-benzyl-2(4,4-difuorobut-3-enylsulfonyl)-1,3,4-oxadiazole(Compound XII.19). ¹ H NMR: δ 2.60(2H,m); 3.60(2H,t); 4.25(1H,m);4.30(2H,s); 7.25-7.40(5H,m); (oil).

(xiii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-pentyl-1,3,4-oxadiazole(Compound XII.27). ¹ H NMR: δ 0.95(3H,t); 1.30-1.45(4H,m);1.80-1.90(2H,m); 2.60-2.70(2H,m); 3.00(2H,t); 3.60(2H,t); 4.30(1H,m);(oil).

(xiv) 5-butyl-2-(4,4-difluorobut-3-enylsulfonyl)-1,3,4-oxadiazole(Compound XII.30). ¹ H NMR: δ 1.00(31H,t); 1.401.50(2H,m);1.80-1.90(2H,m); 2.60-2.70(2H,m); 3.00(2H,t); 3.60(2H,t); 4.30(1H,m);(oil).

(xv) 2-(4,4-difluorobut-3-enylsulfonyl!-5-propyl-1,3,4-oxadiazole(Compound XII.33). ¹ H NMR: δ 1.10(3H,t); 1.85-2.00(2H,m);2.60-2.70(2H,m); 2.95(2H,t); 3.60(2H,t); 4.30(1H,m); (oil).

(xvi) 2-(4,4-difluorobut-3-enylsulfonyl)5-methyl-1,3,4-oxadiazole(Compound XII.51). ¹ H NMR: δ 2.20-2.30(2H,m); 2.30(3H,s); 3.60(2H,t);4.30(1H,m); (oil).

(xvii)2(4,4-difluorobut-3-enylsulfonyl)-5-(2-methylphenyl)-1,3,4-oxadiazole(Compound XII.130). ¹ H NMR: δ 2.70-2.80(2H,m); 2.75(3H,s); 3.70(2H,t);4.30(1H,m); 7.40(1H,d); 7.50(1H,d); 8.00(1H,d); (mp 90-93° C.).

(xviii)2-(4,4-difluorobut-3-enylsulfonyl)-5-(4-nitrophenyl)-1,3,4-oxadiazole(Compound XII.143). M⁺ =345; ¹ H NMR: δ 2.70-2.80(2H,m); 3.70(2H,t);4.35(1H,m); 8.35(2H,d); 8.45(2H,d); (oil).

(xix)2-(4,4-difluorobut-3-enylsulfonyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole(Compound XII.146). ¹ H NMR: δ 2.70-2.80(2H,m); 3.65(2H,t); 3.90(3H,s);4.30(1H,m); 7.05(2H,d); 8.10(2H,d); (mp 60° C.).

EXAMPLE XIII.1

This Example illustrates a general procedure for the preparation of2-(4,4-difuorobut-3-enylthio)-5-substituted-1,3,4-thiadiazoles from thecorresponding thiadiazole-2(3H)-thione, compounds which are well knownin the art. The process is illustrated by the preparation of2-(4,4-difluorobut-3-enylthio)-5-methylamino-1,3,4-thiadiazole (CompoundXIII.70) from the corresponding thione and 4,4difluorobut-3-enyl4-methyl-benzenesulfonate. Other alkylating agents, for example4-bromo-1,1-difluorobut-1-ene may also be used.

Preparation of Compound XIII.70.

To a solution of 5-methylamino-1,3,4-thiadiazole-2(3H)-thione (0.393 g)in acetone (10cm³) was added potassium carbonate (0.369 g) and4,4-difluorobut-3-enyl 4-methylbenzenesulfonate (0.7 g) and the mixturewas heated under reflux for 3 hours after which gc analysis indicatedcomplete consumption of starting material. The reaction mixture wasfiltered through hi-flo filter aid and the pad washed thoroughly withdiethyl ether. The filtrate was poured into ether and water and thelayers were separated. The aqueous layer was extracted twice with etherand the combined organic phases were dried (MgSO₄). Evaporation ofsolvent under reduced pressure gave a brown oil which was purified byflash chromatography on silica gel, eluting with 1:1 ethylacetate:hexane to give Compound XIII.70 (0.273 g) M⁺ =237; ¹ H NMR: δ2.43(2H,m); 3.04(3H,s); 3.15(2H,t); 4.29(1H,m); 5.36(1H,br s); (mp52.5-53.5° C.).

The following compounds according to the invention were prepared by theabove general method using the appropriate mercapto thiadiazoles and insome cases 4-bromo-1,1-difluorobut-1-ene as alkylating agent.

(i) 5-cyclopropyl-2-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole(Compound XIII.6). M⁺ =248; ¹ H NMR: δ 1.10-1.30(4H,m); 2.30-2.40(1H,m);2.45-2.55(2H,m);

3.30(2H,t); 4.30(1H,m); (oil).

(ii) 2-(4,4-difluorobut-3-enylthio)-5-phenyl-1,3,4-thiadiazole (CompoundXIII.9). M⁺ =284; ¹ H NMR: δ 2.50-2.65(2H,m); 3.40(2H,t); 4.50(1H,m);7.40-7.50(3H,m); 7.85-7.95(2H,m); (mp 39° C.).

(iii) 2-(4,4-difluorobut-3-enylthio)-5-isopropyl-1,3,4-thiadiazole(Compound XIII.16). M⁺ =250; ¹ H NMR: δ 1.40(3H,s); 1.45(3H,s);2.45-2.60(2H,m); 3.35(2H,t); 3.35-3.50(1H,m); 4.30(1H,m); (oil).

(iv) 5-benzyl-2-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole (CompoundXIII.20).

M³⁰ =298; ¹ H NMR: δ 2.45-2.55(2H,m); 3.30(2H,t); 4.30(1H,m);4.40(2H,s); 7.25-7.40(5H,m); (oil).

(v) 2(4,4-difluorobut-3-enylthio)-5-methyl-1,3,4-thiadiazole (CompoundXIII.40).

M⁺ =222; ¹ H NMR: δ 2.50(2H,m); 2.73(3H,s); 3.35(2H,t); 4.29(1H,m);(oil).

(vi) 2-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole-5-carboxamide(Compound XIII.45). M⁺ =151; ¹ H NMR: δ 2.50-2.60(2H,m); 3.45(2H,t);4.30(1H,m); 6.80(1H,br s); 7.15(1H,br s); (mp 168° C.).

(vii) 2-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole (CompoundXIII.63). M⁺ =208; ¹ H NMR: δ 2.54(2H,m); 3.43(2H,t); 4.30(1H,m);9.03(1H,s); (oil).

(viii) 5-amino-2-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole(Compound XIII.69). M⁺ =223; ¹ H NMR: δ 2.45(2H,m); 3.20(2H,t);4.30(1H,m); 5.20(2H,br s); (mp 138° C.).

(ix)2-(4,4-difluorobut-3-enylthio)-5-(3-trifluoromethylbenzylthio)-1,3,4-thiadiazole(Compound XIII.110). M⁺ =304; ¹ H NMR: δ 2.51(2H,m); 3.31(2H,t);4.27(1H,m); 4.56(2H,s); 7.42-7.70(4H,m); (oil).

(x)5-cyclopropylmethylthio-2-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole(Compound XIII.114). M⁺ =294; ¹ H NMR: δ 0.35(2H,m); 0.65(2H,m);1.25(1H,m); 2.50(2H,m); 3.25(2H,d); 3.30(2H,t); 4.25(1H,m); (oil).

(xi) 2,5-bis-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole (CompoundXIII.117). M⁺ =330; ¹ H NMR: δ 2.51(4H,m); 3.32(4H,t); 4.29(2H,m);(oil).

(xii) 2-(4,4-difluorobut-3-enylthio)-5-methylthio-1,3,4-thiadiazole(Compound XIII.119). M³⁰ =254; ¹ H NMR: δ 2.51(2H,m); 2.77(3H,s);3.31(2H,t); 4.20(1H,m); (oil).

(xiii)2-(4,4-difluorobut-3-enylthio)-5-(sulfonamidophenyl)-1,3,4thiadiazole(Compound XIII.143). M⁺ =363; ¹ H NMR: δ 2.55-2.65(2H,m); 3.50(2H,t);4.30(1H,m); 4.95(2H,brs); 8.05(4H,m); (mp 154° C.).

EXAMPLE XIII.2

This Example illustrates a general procedure for the preparation of2-(4,4-difluorobut-3-enylthio)-5-substituted-1,3,4-thiadiazoles from2-amino-5-substituted thiadiazoles. The process is illustrated by thepreparation of 2-(4,4difluorobut-3-enylthio)-5-ethyl-1,3,4-thiadiazole(Compound XIII.27) from 2-amino-5-ethyl-1,3,4-thiadiazole.

Preparation of Compound XIII.27.

A solution of 2-amino-5-ethyl-1,3,-thiadiazole (0.786 g) anddi-4,4-difluorobut-3-enyl disulfide (1.5 g) in dichloromethane (25cm³)was stirred and cooled in an ice-water bath. Tert. butyl nitrite (1.2 g)was added, the cold bath removed and the reaction heated under refluxfor 1.3 hours. The mixture was then poured into diethyl ether/water andthe layers separated. The aqueous layer was extracted with ether and thecombined organic phases were dried (MgSO₄), filtered, and evaporatedunder reduced pressure to give a brown oil. Purification by columnchromatography on silica gel using 1:9 and 2:8 ethyl acetate:hexane aseluant gave Compound XIII.27(0.959 g). M⁺ =236; ¹ H NMR: δ 1.40(3H,t);2.45-2.60(2H,m); 3.10(2H,q); 3.35(2H,t); 4.30(1H,m); (oil).

The following compounds according to the invention were prepared by theabove procedure, using the appropriate intermediates:

(i) 5-bromo-2-(4,4-difluorobut-3-enylthio)-1,3,4-thiadiazole (CompoundXIII.1). M⁺ =286; ¹ H NMR: δ 2.45-2.60(2H,m); 3.40(2H,t); 4.30(1H,m);(oil).

(ii) 2-(4,4-difluorobut-3-enylthio)-5-tert.-butyl-1,3,4-thiadiazole(Compound XIII.3).

M⁺ =264; ¹ H NMR: δ 1.48(9H,s); 2.45-2.60(2H,m); 3.35(2H,t); 4.30(1H,m);(oil).

(iii) 2-(4,4difluorobut-3-enylthio)-5-trifluoromethyl-1,3,4-thiadiazole(Compound XIII.14). M⁺ =276; ¹ H NMR: δ 2.50-2.60(2H,m); 3.45(2H,t);4.30(1H,m); (oil).

EXAMPLE XIII.3

This Example illustrates a preparation of2,5-bis-(4,4-difluorobut-3-enylsulfinyl)-1,3,4-thiadiazole (CompoundXIII.133) using 3-chloroperbenzoic acid as the oxidant

A solution of Compound XIII.117(0.49 g) in dichloromethane (30cm³) wascooled in a methanol ice bath to ˜-10° C., 3-chloroperbenzoic acid (1 gof a 50% by weight solid, 2 equivalents) was added and the reaction wasallowed to stir and gradually warm to the ambient temperature, thenstirred for 7 hours and left to stand for 18 hours. The mixture was thenpoured into sodium bicarbonate solution and the product extracted intodiethyl ether. The combined organic phases were washed with sodiumbicarbonate solution and dried (MgSO₄). Evaporation of solvent underreduced pressure gave a pale yellow liquid which was purified by flashchromatography on silica gel, eluting with 30% ethyl acetate in hexaneto give Compound XIII.133(0.168 g). M⁺ =362; ¹ H NMR: δ 2.58(4H,m);3.36(4H,m); 4.26(2H,m). (mp 46-48° C.).

The following compounds according to the invention were prepared by theabove general procedure, using the appropriate number of equivalents of3-chloroperbenzoic acid as oxidant.

(i) 2-(4,4-difluorobut-3-enylsulfinyl)-5-phenyl-1,3,4-thiadiazole(Compound XIII.10). M⁺ =300; ¹ H NMR: δ 2.40-2.80(2H,m);3.30-3.40(2H,m); 4.30(1H,m); 7.45-7.60(3H,m); 7.95-8.00(2H,m); (mp 67°C.).

(ii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-phenyl-1,3,4-thiadiazole(Compound XIII.11). M⁺ =316; ¹ H NMR: δ 2.60-2.75(2H,m); 3.65(2H,t);4.30(1H,m); 7.45-7.65(3H,m); 7.95-8.05(2H,m); (mp 80° C.).

(iii) 2-(4,4-difluorobut-3-enylsulfinyl)-5-methyl-1,3,4-thiadiazole(Compound XIII.41). M⁺ =238; ¹ H NMR: δ 2.35-2.55(1H,m);2.55-2.75(1H,m); 2.90(3H,s); 3.20-3.40(2H,m); 4.30(1H,m); (oil).

(iv) 2-(4,4-difluorobut-3-enylsulfonyl)-5-methyl-1,3,4-thiadiazole(Compound XIII.42). M⁺ =255; ¹ H NMR: δ 2.55-2.70(2H,m); 2.95(3H,s);3.60(2H,t); 4.30(1H,m); (oil).

(v) 2-(4,4-difluorobut-3-enylsulfinyl)-1,3,4thiadiazole (CompoundXIII.64). M³⁰ =225; ¹ H NMR: δ 2.35-2.50(1H,m); 2.60-2.75(1H,m);3.25-3.45(2H,m); 4.30(1H,m); 9.35(1H,s); (oil).

(vi) 2-(4,4-difluorobut-3-enylsulfonyl)-1,3,4-thiadiazole (CompoundXIII.65). MH⁺ =241; ¹ H NMR: δ 2.60-2.70(2H,m); 3.70(2H,t); 4.30(1H,m);9.40(1H,s); (oil).

(vii) 2,5-bis-(4,4-difluorobut-3-enylsulfonyl)-1,3,-thiadiazole(Compound XIII.124). M⁺ =394; ¹ H NMR: δ 2.69(4H,m); 3.70(4H,t);4.30(2H,m); (mp 88-91° C.).

(viii)2-(4,4-difluorobut-3-enylsulfonyl)-5-(4,4-difluorobut-3-enylsulfinyl)-1,3,4-thiadiazole(Compound XIII.134). M⁺ =378; ¹ H NMR: δ 2.38-2.55(1H,m);2.60-2.79(3H,m); 3.38(2H,m); 3.62-3.74(2H,m); 4.19-4.39(2H,m); (mp45-47° C.).

The following compounds according to the invention were prepared by theabove general procedure but using the appropriate number of equivalentsof magnesium monoperoxyphthalate as oxidant.

(ix) 5-bromo-2-(4,4-difluorobut-3-enylsulfonyl)-1,3,4-thiadiazole(Compound XIII.2). MH⁺ =319; ¹ H NMR: δ 2.60-2.70(2H,m); 3.65(2H,t);4.30(1H,m); (oil).

(x) 2-(4,4-difluorobut-3-enylsulfonyl)-5-tert.-butyl-1,3,4-thiadiazole(Compound XII.4). MH⁺ =297; ¹ H NMR: δ 1.55(9H,s); 2.60-2.70(2H,m);3.65(2H,t); 4.30(1H,m); (mp 37° C.).

(xi) 5-cyclopropyl-2-(4,4-difluorobut-3-enylsulfonyl)-1,3,4-thiadiazole(Compound XIII.7). MH⁺ =281; ¹ H NMR: δ 1.25-1.45(4H,m);2.40-2.55(1H,m); 2.55-2.65(2H,m); 3.60(2H,t); 4.30(1H,m); (gum).

(xii)2-(4,4-difluorobut-3-enylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole(Compound XIII.15). M-SO₂ H⁺ =243; ¹ H NMR: δ 2.60-2.75(2H,m);3.75(2H,t); 4.20-4.40(1H,m); (gum).

(xiii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-isopropyl-1,3,4-thiadiazole(Compound XIII.17).

M⁺ =283; ¹ H NMR: δ 1.50(3H,s); 1.55(3H,s); 2.60-2.70(2H,m);3.50-3.70(3H,m); 4.30(1H,m); (mp 43° C.).

(xiv) 2-(4,4-difluorobut-3-enylsulfinyl)-5-ethyl-1,3,4-thiadiazole(Compound XIII.28). ¹ H NMR: δ 1.50(3H,t); 2.40-2.50(1H,m);2.60-2.70(1H,m); 3.20(2H,q); 3.25-3.35(2H,m); 4.25(1H,m); (gum).

(xv) 2-(4,4-difluorobut-3-enylsulfonyl)-5-ethyl-1,3,4-thiadiazole(Compound XII.29). M⁺ =269; ¹ H NMR: δ 1.50(3H,t); 2.6-2.70(2H,m);3.20(2H,q); 3.65(2H,t); 4.30(1H,m); (gum).

EXAMPLE XIII.4

This Example illustrates a preparation of2-(4,4difluorobut-3-enylthio)-5-methoxy-1,3,4thiadiazole (CompoundXIII.101) from Compound XIII.1.

To a stirred suspension of sodium hydride (0.030 g) in toluene (3 cm³)was added methanol (0.022 g), resulting in effervescence. After stirringfor 10 minutes, Compound XII.1(0.20 g) was added and the reaction wasstirred at the ambient t for 18 hours. The reaction was analysed by gcand further portions of sodium hydride and methanol added until completeloss of starting material was observed. The reaction was poured intowater and the layers separated. The product was extracted into diethylether and the combined organic phases were dried (MgSO₄) filtered andevaporated under reduced pressure to give a pale yellow oil.Purification by column chromatography on silica gel using 3:17ether:hexane as the eluant gave Compound XIII.101(0.069 g). M⁺ =238; ¹ HNMR: δ 2.40-2.55(2H,m); 3.25(2H,t); 4.20(3H,s); 4.30(1H,m); (oil).

EXAMPLE XIV.1

This Example illustrates the preparation of5-(4,4-difluorobut-3-enylthio)-1-methyltetrazole (Compound XIV.1).

The sodium salt of 5-mercapto-1-methyltetrazole was alkylated with4bromo-1,1-difluorobut-1-ene using the procedure of Example XIII.1 togive Compound XIV.1. M⁺ =206; ¹ H NMR: δ 2.53(2H,m); 3.38(2H,t);3.92(3H,s); 4.28(1H,m); (oil).

EXAMPLE XV.1

This example illustrates a preparation of1-(4,4-difluorobut-3-enylthio)-4-nitrobenzene (Compound XV.1).4Nitro-thiophenol (0.5 g), potassium carbonate (0.448 g),4,4-difluorobut-3-enyl 4-methyl-benzenesulfonate (0.846 g) and potassiumiodide (0.388 g) were heated and stirred under reflux in acetone (15cm³) for a total of 6 hours after which none of the starting tosylatewas detectable by tlc. The reaction mixture was poured into water andextracted with 3 portions of ethyl acetate. The combined organic phaseswere washed 3 times with 2M NaOH and saturated aqueous brine and thendried (MgSO₄). Removal of solvent by evaporation under reduced pressuregave a dark yellow oil which was purified by flash chromatography onsilica gel using 5% ethyl acetate in hexane as eluant to give CompoundXV.1(0.474 g). M³⁰ =245; ¹ H NMR: δ 2.42(2H,m); 3.09(2H,t); 4.30(1H,m);7.35(2H,d); 8.14(2H,d); (oil).

EXAMPLE XVI.1

This Example illustrates a preparation of2-chloro-4-(4,4-difluorobut-3-enylthio)-pyridine (Compound XVI.1).

Tert-butyl nitrite (0.442 g) in dichloromethane (20 cm³) was addeddropwise to a solution of 4-amino-2-chloropyridine andbis-(4,4-difluorobut-3-enyl)disulfide (1.9 g) in dichloromethane (20cm³) while stirring the mixture at 0° C. The reaction mixture wasstirred for 4 hours and then allowed to stand at the ambient temperaturefor 18 hours. Water was added and the product extracted into ethylacetate. The combined organic phases were washed with saturated brine,dried (MgSO₄), filtered and evaporated under reduced pressure to give anorange-brown gum. Chromatography on sorbsil-C30 using 4% ethyl acetatein hexane as eluant gave Compound XVI.1(0.134 g). M⁺ =235; ¹ H NMR: δ2.35-2.46(2H,m); 2.98-3.7(2H,t); 4.18(1H,m); 7.02(1H,d); 7.11(1H,d);8.14-8.21(1H,d); (oil).

EXAMPLE XVI.2

This Example illustrates a 2-step preparation of4-(4,4-difluorobut-3-enylthio)-2,3,5,6-tetrafluoropyridine (CompoundXVI.2).

Step 1: Preparation of the sodium salt of2,3,5,6-tetrafluoropyridine-4-thiol 4-Chloro-2,3,5,6-tetrafluoropyridine(2 g) and sodium hydrosulfide dihydrate were stirred and heated underreflux in iso-propanol (40 cm³) for 3 hours. The mixture was thenstirred at the ambient temperature for 18 hours. The precipitated solidwas removed by filtration, washed with diethyl ether and discarded. Thecombined organic solutions were evaporated under reduced pressure togive 2,3,5,6-tetrafluoropyridine-4-thiol as its sodium salt (2.21 g),which was used without further purification in the second step.

Step 2: Preparation of (Compound XVI.2)

The intermediate from step 2(1.7 g), 4-bromo-1,1,-difluorobut-1-ene(1.99 g), and potassium carbonate (1.53 g), were stirred and heatedunder reflux in acetone (30 cm³) for 18 hours. The inorganic precipitatewas removed by filtration and the filtrate evaporated under reducedpressure to give a dark brown oil. Chromatography on sorbsil-C30 usinghexane as eluant gave Compound XVI.2(1.82 g). M⁺ =273; ¹ H NMR: δ2.3-2.42(2H,m); 3.15-3.25(2H,t); 4.154.34(1H,m); (oil).

The following compounds according to the invention were prepared usingthe procedure of Step 2 above. The alkylating agent was4-bromo-1,1,-difluorobut-1-ene or 4,4-difluorobut-3-enyl4-methyl-benzenesulfonate.

(i) 4-(4,4difluorobut-3-enylthio)pyridine (Compound XVI.5). M⁺ =201; ¹ HNMR: δ 2.40(2H,m); 3.04(2H,t); 4.30(1H,m); 7.11(2H,d); 8.41(2H,d); (oil)from 4-mercaptopyridine.

(ii) 4,4-difluorobut-3-enyl2-(4,4difluorobut-3-enylthio)pyridine-3-carboxylate (Compound XVI.10).M⁺ =335; ¹ H NMR: δ 2.43(4H,m); 3.22(2H,t); 4.29(2H,m); 4.36(2H,t);7.09(1H,dd); 8.20(1H,dd); 8.57(1H,dd); (oil) from2-mercaptopyridine-3-carboxylic acid. Potassium iodide was used toconvert two equivalents of 4,4-difluorobut-3-enyl4-methyl-benzenesulfonate to the more reactive4-iodo-1,1-difluorobut-1-ene in situ in this reaction.

(iii) 2-(4,4difluorobut-3-enylthio)-5-trifluoromethylpyridine (CompoundXVI.11). ¹ H NMR: δ 2.40(2H,m); 3.25(2H,t); 4.25(1H,m); 7.25(1H,dd);7.45(1H,dd); 8.40(1H,d); (oil) from2-mercapto-5-trifluoromethylpyridine.

(iv) 2-(4,4-difluorobut-3-enylthio)pyridine (Compound XVI.19). M⁺ =201;¹ H NMR: δ 2.40(2H,m); 3.20(2H,t); 4.30(1H,m); 6.90(1H,dd); 7.20(1H,dd);7.45(1H,td); 8.40(1dd); (oil).

(v) 2-(4,4-difluorobut-3-enylthio)-5-nitropyridine (Compound XVI.21). M⁺=246; ¹ H NMR: δ 2.45(2H,m); 3.30(2H,t); 4.28(1H,m); 7.30(1H,d);8.23(1H,dd); 9.25(1H,d);

(oil) from 2-mercapto-5-nitropyridine.

EXAMPLE XVI.3

This Example gives a general procedure for the preparation of2-(4,4-difluorobut-3-enylthio)-5-substituted-pyridines from2-chloro-5-substituted-pyridines. The method is illustrated by thepreparation of 5-chloro-2-(4,4-difluorobut-3-enylthio)pyridine (CompoundXVI.13) from 2,5-dichloropyridine.

Sodium hydrosulfide dihydrate (0.672 g) was added to a solution of2,5-dichloropyridine (1.48 g) in dimethylformamide (20 cm³), causing themixture to go blue and then green on heating to 100° C. The reaction washeated for 7 hours and then 4-bromo-1,1-difluorobut-1-ene (1.71 g) andpotassium carbonate (1.38 g) were added. The reaction was heated for 2hours then allowed to cool. The reaction mixture was poured into diethylether and 2M HCl and the layers separated. The aqueous layer wasextracted with ether. The combined organic phases were then washed with2M HCl, water and brine (alternately 3 times each), dried (MgSO₄),filtered and evaporated under reduced pressure to give a brown oil.Column chromatography on silica gel using 2% diethyl ether in hexane aseluant gave Compound XVI.13 (0.805 g). M⁺ =235; ¹ H NMR: δ 2.40(2H,m);3.20(2H,t); 4.25(1H,m); 7.15(1H,dd); 7.45(1H,dd); 8.40(1H,d); (oil).

The following compound according to the invention was prepared using theabove procedure:

(i) 5-cyano-2-(4,4-difluorobut-3-enylthio)pyridine (Compound XVI.15). ¹H NMR: δ 2.40(2H,m); 3.25(2H,t); 4.25(1H,m); 7.25(1H,dd); 7.70(1H,dd);8.65(1H,d); (mp 34° C.).

EXAMPLE XVI.4

This Example gives a general procedure for the preparation of2-(4,4-difluorobut-3-enylthio)-3-substituted-pyridines from2-chloro-3-substituted-pyridines and 4,4-difuorobut-3-enylisothiouroniumhydrobromide. The method is illustrated by the preparation of2-(4,4-difluorobut-3-enylthio)-3-nitropyridine (Compound XVI.24) from2-chloro-3-nitropyridine.

4,4-Difluorobut-3-enylisothiouronium hydrobromide (1.24 g) was added toa solution of sodium hydroxide (0.6 g) in water (10 cm³) and thereaction was Sired vigorously at the ambient temperature for 20 minutes.A solution of 2-chloro-3-nitropyridine (0.795 g) in dichloromethane (10cm³) was added to the reaction followed by tetra-n-butylammonium bromide(catalytic). The reaction was stirred vigorously for 3 hours. Themixture was diluted with dichloromethane and the layers separated. Theorganic layer was washed with brine, dried (MgSO₄), filtered, andevaporated under reduced pressure to give a yellow oil. Columnchromatography on silica gel using 15% diethyl ether in hexane as eluantgave Compound XVI.24 (0.847 g). M⁺ =246; ¹ H NMR: δ 2.40(2H,m);3.25(2H,t); 4.30(1H,m); 7.20(1H,dd); 8.50(1H,dd); 8.70(1H,dd); (oil).

The following compound according to the invention was prepared using theabove procedure:

(i) 3-cyano-2-(4,4-difluorobut-3-enylthio)pyridine (Compound XVI.8). M⁺=226; ¹ H NMR: δ 2.40(2H,m); 3.30(2H,t); 4.25(1H,m); 7.10(1H,dd);7.80(1H,dd); 8.55(1H,dd); (oil).

EXAMPLE XVI.5

This Example illustrates a method suitable for the preparation ofcompounds according to the invention in which the sulfur atom of the4,4-difluorobut-3-enylthio substituent of the corresponding unoxidisedcompound (prepared according to the procedures of the precedingExamples) is oxidised to sulfoxide (sulfinyl) or sulfone (sulfonyl).

Preparation of Compound XVI.3 from Compound XVI.2 using one equivalentof oxidant.

Compound XVI.2 (0.818 g) was cooled to 0° C. in dichloromethane (30 cm³)and 3-chlorobenzoic acid (0.99 g) was added over a period of fiveminutes. The mixture was stirred at the ambient temperature for 6 hourand stood for 40 hours. The reaction mixture was poured into saturatedaqueous sodium bicarbonate and the product was extracted intodichloromethane. The organic layer was washed with water and dried(MgSO₄). Evaporation of solvent under reduced pressure gave a yellow oilwhich was chromatographed on sorbsil-C30, eluting with 15% ethyl acetatein hexane to give4-(4,4-difluorobut-3-enylsulfinyl)-2,3,5,6-tetrafluoropyridine (0.711g). ¹ H NMR: δ 2.45-2.8(2H,m); 3.15-3.3(1H,m); 3.5-3.65(1H,m);4.2-4.4(1H,m); (oil).

Preparation of 5-cyan-2-(4.4-difluorobut-3-enylsulfonyl)pyridine(Compound XVI.16) from Compound XVI.15 using two equivalents of oxidant.

3-Chloroperbenzoic acid (3.14 g of a 50% solid) was added portionwise toa stirred solution of Compound XVI.15 (1.03 g) in dichloromethane (30cm³) at 0° C. The reaction was then allowed to warm to the ambienttemperature and stirred for 4 hours. The m was poured into 2M aqueoussodium hydroxide and the layers separated. The aqueous layer wasextracted with dichloromethane and the combined organic layers weredried over magnesium sulfate, filtered and evaporated under reducedpressure to give a yellow oil which crystallised on standing. Columnchromatography on silica gel using 3:7 ethyl acetate:hexane as eluantgave Compound XVI.16 (0.785 g). ¹ H NMR: δ 2.40(2H,m); 3.25(2H,t);4.25(1H,m); 7.25(1H,dd); 7.70(1H,dd); 8.65(1H,d); (mp 34° C.)

The following compounds according to the invention were prepared usingthe above procedure:

(i) 4-(4,4-difluorobut-3-enylsulfonyl)pyridine (Compound XVI.6). ¹ HNMR: δ 2.50(2H,m); 3.20(2H,t); 4.25(1H,m); 7.80(2H,d); 8.95(2H,d);(oil).

(ii) 2-(4,4-difluorobut-3-enylsulfonyl)-5-trifluoromethylpyridine(Compound XVI.12). ¹ H NMR: δ 2.50(2H,m); 3.50(2H,t); 4.25(1H,m);8.25(2H,d); 9.00(1H,br s); (mp 60° C.).

(iii) 2-(4,4-difluorobut-3-enylsulfonyl)pyridine (Compound XVI.20). ¹ HNMR: δ 2.50(2H,m); 3.50(2Ht); 4.25(1H,m); 7.55-7.50(1Hm); 8.00(1H,dt);8.10(1H,d); 8.75(1H,d); (oil).

EXAMPLE XVII.1

This Example illustrates a 2-step preparation of3-(4,4-difluorobut-3-enylthio)-6-methylpyridazine (Compound XVII.1).

Step 1: Preparation of 3-mercapto-6-methylpyridazine

3-Chloro-6-methylpyridazine (5 g) and thiourea (2.96 g) were stirredtogether and heated under reflux in ethanol (50 cm³) for 7.5 hours. Thereaction was cooled and allowed to stand for 18 hours. The solidprecipitate which had formed was filtered off and washed with diethylether to give 3-mercapto-6-methylpyridazine (2.3 g), which was used inthe next step without further purification. ¹ H NMR: δ 2.40(3H,s);7.30(1H,d); 7.63(1H,d); 14.5-14.7(1H,br s).

Step 2: Preparation of Compound XVII.1

A mixture of the product from Step 1 (0.337 g), 4,4-difluorobut-3-enyl4-methylbenzenesulfonate (0.70 g), potassium iodide (0.444 g) andpotassium carbonate (0.369 g) were stirred together and heated underreflux in acetone (20 cm³) for 11 hours. Inorganic solids were removedby filtration and the filtrate evaporated under reduced pressure to givea brown oil. Chromatography on silica gel using 1:4 ethyl acetate:hexaneas eluant gave Compound XVII.1 (0.15 g). M⁺ =216; ¹ H NMR: δ 2.48(2H,m);2.62(3H,s); 3.36(2H,t); 4.20-4.40(1H,m); 7.10(1H,d); 7.21(1H,d); (oil).

The following compounds according to the invention and the correspondingintermediate compounds were prepared using the procedure of Steps 1 and2 above.

(i) 3-(4,4-difluorobut-3-enylthio)-6-chloropyridazine (Compound XVII.2).M⁺ =236; ¹ H NMR: δ 2.50(2H,m); 3.39(2H,t); 4.20-4.40(1H,m); 7.27(2H,s);(oil) from 3,6-dichloropyridazine.

(ii) 3-(4,4-difluorobut-3-enylthio)-6-methoxypyridazine (CompoundXVII.3). M⁺ =232; ¹ H NMR: δ 2.47(2H,m); 3.31(2H,t); 4.09(3H,s);4.20-4.40(1H,m); 6.83(1H,d); 7.20(1H,d); (solid mp 39.3-40.1° C.) from3-chloro-6-methoxypyridazine.

(iii) 3-(4,4-difluorobut-3-enylthio)-6-phenylpyridazine (CompoundXVII.4). M⁺ =278; ¹ H NMR: δ 2.54(2H,m); 3.46(2H,t); 4.25-4.42(1H,m);7.39(1H,d); 7.51(3H,m); 7.69(1H,d); 8.05(2H,m); (solid mp 91.7-92.1° C.)from 3-chloro-6-phenylpyridazine.

(iv) 1-(4,4-difluorobut-3-enylthio)-phthalazine (Compound XVII.7). M⁺=252; ¹ H NMR (CDCl₃): δ 2.59(2H,m); 3.55(2H,t); 4.28-4.45(1H,m);7.89(3H,m); 8.12(1H,m); 9.25(1H,s); (oil) from 1(2H)-phthalazinthioneusing the procedure of Step 2 above.

EXAMPLE XVII.2

This Example illustrates a preparation of Compounds XVII.5 and XVII.6from Compound XVII.4.

Compound XVII.4 (0.5 g) was stirred at ambient temperature inisopropanol (20 cm³) and magnesium monoperoxyphthalic acid hexahydrate(0.89 g in 10 cm³ water) was added. The mixture was stirred at theambient temperature for 20 hours. The solid which had precipitated wasfiltered off and washed with water. The filtrate was poured into asaturated aqueous solution of sodium bicarbonate and further product wasextract into ethyl acetate. The combined organic layers were washed withsaturated brine and dried (NgSO₄). Evaporation of solvent under reducedpressure gave an off-white solid which was combined with the materialfirst precipitated and chromatographed on silica gel, eluting with 30%ethyl acetate in hexane. The first product recovered was3-(4,4-difluorobut-3-enylsufonyl)-6-phenylpyridazine (Compound XVII.6)(0.2 g). M⁺ =310; ¹ H NMR: δ 2.60(2H,m); 3.75(2H,t); 4.20-4.40(1H,m);7.60(3H,m); 8.11(1H,d); 8.15(2H,m); 8.22(1H,d); (solid mp 141.7-144.3°C.) Further elution gave3-(4,4-difluorobut-3-enylsufonyl)-6phenylpyridazine (Compound XVII.5)(0.25 g). M⁺ =294; ¹ H NMR: δ 2.40 and 2.65(2H,m); 3.20-3.40(2H,m);4.18-4.32(1H,m); 7.59(3H,m); 8.11(1H,d); 8.15(2H,m); 8.21(1H,d); (mp133-134° C).

EXAMPLE XVIII.1

This Example illustrates a 3-step preparation of2-(4,4-difluorobut-3-enylthio)-quinoxaline (Compound XVIII.1).

Step 1: Preparation of quinoxalin-2-thione

2-Quinoxalinol (10 g), phosphorous pentasulfide (16.72 g) and pyridine(200 cm³) were stirred together and heated under reflux for 7 hours. Thereaction mixture was allowed to cool and most of the pyridine wasremoved by evaporation under reduced pressure. The residue waspartitioned between ethyl acetate and water and the organic layer wasseparated. The aqueous layer was extracted with three further portionsof ethyl acetate and the combined organic phases were washed withsaturated aqueous brine, dried (MgSO₄) and evaporated under reducedpressure to give a brown oily solid which was triturated with hot ethylacetate:hexane (1:1) to dissolve the product and leave an insolubleresidue. The solvent was removed under reduced pressure and gave anorange solid, part of which was used without further purification inStep 2.

Step 2: Preparation of 2-(4bromo-4,4-difluorobutylthio)-quinoxaline

A mixture of the product from Step 1 (1 g), 4-bromo-4,4-difluorobutylmethanesulfonate (1.65 g) and potassium carbonate (0.852 g) were stirredtogether in acetone (30 cm³) at ambient temperature for 7 hours.Inorganic solids were removed by filtration and the filtrate evaporatedunder reduced pressure to give a brown oil. Chromatography on silica gelusing 1:4 ethyl acetate:hexane as eluant gave2-(4-bromo-4,4-difluorobutylthio)-quinoxaline (1.375 g). M⁺ =332; ¹ HNMR: δ 2.19(2H,m); 2.50-2.70(2H,m); 3.43(2H,t); 7.60-7.73(2H,m);7.93(1H,dd); 8.03(1H,dd); 8.60(1H,s); (oil).

Step 3: Preparation of Compound XVIII.1

1,8-Diazabicyclo 5.4.0! undec-7-ene (DBU) (1.14 cm³) and the productfrom step 2 (1.275 g) were stirred in toluene (30 cm³) and heated underreflux for 5 hours. The mixture was cooled, then excess ethyl acetateand 2M aqueous hydrochloric acid were added and the organic phaseseparated. The aqueous phase was extracted with ethyl acetate and thecombined organic phases were washed with saturated brine, dried (MgSO₄),filtered and evaporated under reduced pressure to give a brown oil.Chromatography on silica gel using 1:4 ethyl acetate:hexane as eluantgave Compound XVIII.1(0.65 g). M³⁰ =252; ¹ H NMR: δ 2.51(2H,m);3.39(2H,t); 4.30-4.40(1H,m); ⁷.60-7.75 (2H,m); 7.90(1H,dd); 8.03(1H,dd);8.60(1H,s); (oil).

The following compound according to the invention and the correspondingintermediate compound were prepared using the procedure of Steps 2 and 3above:

(i) 6-chloro-2-(4,4-difluorobut-3-enylthio)quinoxaline (CompoundXVIII.4). M⁺ =286; ¹ H NMR: δ 2.50(2H,m); 3.35(2H,t); 4.20-4.40(1H,m);7.65(1H,dd); 7.86(1H,d); 8.01(1H,d); 8.59(1H,s); (oil), from6-chloroquinoxalin-2-thione via2-(4-bromo-4,4-difluorobutylthio)-6-chloroquinoxaline. ¹ H NMR: δ2.08-2.21(2H,m); 2.48-2.68(2H,m); 3.40(2H,t); 7.65(1H,dd); 7.88(1H,d);8.00(1H,d); 8.60(1H,s); (oil).

EXAMPLE XVIII.2

This Example illustrates a 2-step preparation of2-(4,4-difluorobut-3-enylthio)pyrazine (Compound XVIII.7).

Step 1: Preparation of 2-mercaptopyrazine

2-Chloropyrazine (5 g) and thiourea (3.32 g) were heated under reflux inethanol (50 cm³) for 8 hours. The reaction mixture was cooled and theethanol was removed by evaporation under reduced pressure to give abrown gum (8.31 g) which was stirred with 2M aqueous sodium hydroxide(50 cm³) for 16 hours. The solid which precipitated was filtered off andwashed with water and acetone and vacuum dried. This gave a yellow solid(0.72 g); ¹ H NMR (DMSO-d₆): δ 7.69(1H,d); 7.89(1H,d); 8.6(1H,s), whichwas used in the second step without further purification.

Step 2: Preparation of Compound XVIII.7

The product from Step 1 (0.213 g), 4,4-difluorobut-3-enyl4-methyl-benzenesulfonate (0.5 g), potassium carbonate (0.263 g) andpotassium iodide (0.317 g) were mixed in acetone (10 cm³) and heatedunder reflux for 9 hours then allowed to cool over a weekend Theprecipitate formed was removed by filtration and the filtrate evaporatedunder reduced pressure to give a brown oil. Chromatography on silica gelusing 1:4 ethyl acetate:hexane as eluant gave Compound XVIII.7 (0.3 g).M⁺ =202; ¹ H NMR: δ 2.40(2H,m); 3.21(2H,t); 4.20-4.40(1H,m); 8.20(1H,d);8.38(1H,t); 8.48(1H,s); (oil).

EXAMPLE XVIII.3

This Example illustrates a 2-step preparation of3-chloro-2-(4,4-difluorobut-3-enylthio)-pyrazine (Compound XVIII.10).

Step 1: Preparation of 2-chloro-3-mercaptopyrazine and2,3-dimercatopyrazine

2,3-Dichloropyrazine (1 g) and sodium hydrosulfide dihydrate (2.5 g)were combined in isopropanol (20 cm³) and the mixture heated underreflux for 1 hour. The reaction was cooled and allowed to stand for 36hours. The yellow solid which precipitated was recovered by filtration,washed with diethyl ether and dried under vacuum. The filtrate wasdiscarded. The solid was dissolved in hot ethanol and on cooling a smallamount of sodium hydrosulfide precipitated and was removed byfiltration. The remaining ethanol solution was diluted with diethylether whereupon a yellow solid (0.3 g) precipitated. This was identifiedas the bis-sodium salt of 2,3-dimercaptopyrazine, MH⁺ (FAB)=188; ¹ H NMR(DMSO-d₆): δ 7.35(1H,d); 7.50(1H,d). Evaporation of the mother liquorsgave a yellow solid (0.8 g), identified as the sodium salt of2-chloro-3-mercaptopyrazine, M(FAB)=145; ¹ H NMR (DMSO-d₆): δ7.35(1H,d); 7.80(1H,d)

Step 2: Preparation of 3-chloro-2-(4,4-difluorobut-3-enylthio)-pyrazine

The mono-thiolate product from Step 1 (0.8 g), 4,4-difluorobut-3-enyl4-methylbenzenesulfonate (1.24 g) and potassium carbonate (0.655 g) weremixed in acetone (25 cm³) containing dimethyl formamide (5 cm³) andheated under reflux for 15 hours then allowed to cool. The precipitatewas removed by filtration and the filtrate evaporated under reducedpressure to give a brown oil. Chromatography on silica gel using a 95:5mixture of hexane:ethyl acetate as eluant gave Compound XVIII. 10 (0.45g). M⁺ =236; ¹ H NMR: δ 2.41(2H,m); 3.20(2H,t); 4.20-4.40(1H,m);8.05(1H,d); 8.30(1H,d) (oil). This contained (gc) 5% of CompoundXVIII.13 as an impurity.

Compound XVIII.13 was obtained pure in its own right by treatment of thebisthiolated product from Step 1 of the above example with twoequivalents of 4,4-difluorobut-3-enyl 4-methyl-benzenesulfonate underthe same conditions as Step 2 of this Example. Chromatography on silicagel using a 4:1 mixture of hexane:ethyl acetate as eluant gave2.3-bis-(4,4-difluorobut-3-enylthio)-pyrazine. M⁺ =324; ¹ H NMR: δ2.40(4H,m); 3.22(4H,t); 4.20-4.40(2H,m); 8.07(2H,s) (oil).

The following compound according to the invention was prepared using theabove procedure:

(i) 6-chloro-2-(4,4-difluorobut-3-enylthio)-pyrazine (Compound XVIII.14). M⁺ =236; ¹ H NMR: δ 2.42(2H,m); 3.21(2H,t); 4.20-4.40(1H,m);8.20(1H,s); 8.35(1H,s) (oil) from 2,6-dichloropyrazine.

EXAMPLE XVIII.4

This Example illustrates a preparation of Compounds XVIII.2 and XVIII.3from Compound XVIII.1.

Compound XVIII.1 (0.25 g) was stirred at ambient temperature in ethanol(10 cm³) and magnesium monoperoxyphthalic acid hexahydrate (0.589 g in 5cm³ water) was added over a period of five minutes. After 30 minutes,the mixture was heated to 70° C. for 1 hour. The reaction mixture wascooled, poured into saturated aqueous sodium bicarbonate and theproducts were extracted into ethyl acetate. The organic layer was washedwith water and dried (MgSO₄). Evaporation of solvent under reducedpressure gave an off-white solid (0.15 g) which was chromatographed onsilica gel, eluting with 10% ethyl acetate in hexane. The main productrecovered was 2-(4,4-difluorobut-3-enylsulfonyl)-quinoxaline (CompoundXVIII.3) (0.1 g) mp 86.5-87.5° C. M⁺ =284; ¹ H NMR: δ 2.61(2H,m);3.62(2H,t); 4.20-4.40(1H,m); 8.00(2H,m); 8.25(2Hm); 9.51(1H,s). Tlcindicated the presence of a lower rf material,2-(4,4-difluorobut-3-enylsulfinyl)-quinoxaline (Compound XVIII.2) in thecrude reaction product but this was not isolated pure.

The following compounds according to the invention were prepared by theabove procedure:

(i) 6-chloro-2-(4,4difluorobut-3-enylsulfinyl)-pyrazine (CompoundXVIII.15). M⁺ =253; ¹ H NMR: δ 2.30-2.70(2H,m); 3.00-3.30(2H,m);4.19-4.35(1H,m); 8.70(1H,s); 9.10(1H,s) (oil) from Compound XVIII.14.

(ii) 6-chloro-2-(4,4-difluorobut-3-enylsulfonyl)-pyrazine (CompoundXVIII.16). M⁺ =268; ¹ H NMR: δ 2.55(2H,m); 3.50(2H,t); 4.20-4.35(1H,m);8.90(1H,s); 9.19(1H,s) (oil); from Compound XVIII.14.

EXAMPLE VIII.1

This Example illustrates a 3-step preparation of4-(4,4-difluorobut-3-enylthio!-1,2,3-benzotriazine (Compound XIX.1).

Step 1; Preparation of 4mercapto-1,2,3-benzotriazine

2-Aminobenzonitrile (5 g) was stirred in pyridine (30 cm³),triethylamine (6 cm³) was added and hydrogen sulfide gas was bubbledinto the reaction over 4 hours. The mixture was then poured into water(20 cm³) and the oil which separated out on shaking was separated off,and dried by azeotroping with ethanol and toluene. This gave a yellowsolid (2-aminothiobenzamide, 3 g) which was stirred in 2M hydrochloricacid (30 cm³) at 0° C. Sodium nitrite (1.65 g) in water (10 cm³) wasadded dropwise and the reaction mixture was stirred cold for 1 hour,then allowed to warm to the ambient temperature and stirred for a filter1 hour. The solid which was produced was filtered off, washed with waterand dried by washing with diethyl ether, to give a brown solid (2.15 g).

Step 2: Preparation of4-(4,4-difluorobut-3-enylthio)-1,2,3-benzotriazine

The product of Step 1 (1 g), 4,4-bromo-4,4-difluorobutylmethanesulfonate) (1.65 g) and potassium carbonate (0.852 g) werestirred together in acetone (30 cm³) at ambient temperature for 36hours. Inorganic solids were removed by filtration and the filtrateevaporated under reduced pressure to give a brown oil. Chromatography onsilica gel using 1:4 ethyl acetate:hexane as eluant gave two yellow oils(ea 0.5 g). The first-eluted oil was identified as N-alkylated materialand the second was the desired S-alkyated intermediate4)-4-bromo-4,4-difluorobutylthio)-1,2,3-benzotriazine. ¹ H NMR: δ2.18-2.31(2H,m); 2.58-2.71(2H,m); 3.63(2H,t); 7.95(1H,t); 8.09(2H,m);8.40(1H,d).

Step 3: Preparation of Compound XIX.1

1,8-Diazabicyclo 5.4.0! undec-7-ene (DBU) (0.45 cm³) and the productfrom step 2 (0.5 g) were stirred in toluene (15 cm³) and heated underreflux for 6 hours. The mixture was cooled, then excess ethyl acetateand 2M aqueous hydrochloric acid were added and the organic phaseseparated. The aqueous phase was extracted with ethyl acetate and thecombined organic phases were washed with saturated brine, dried overanhydrous magnesium sulfate, filtered and evaporated under reducedpressure to give a yellow oil. Chromatography on silica gel using 1:4ethyl acetate:hexane as eluant gave Compound XIX.1 (0.25 g). MH⁺ =254; ¹H NMR: δ 2.60(2H,m); 3.60(2H,t); 4.30-4.40(1H,m); 7.93(1H,t);8.09(2H,m); 8.39(1H,d); (oil).

EXAMPLE XX.1

Two methods (A and B) of preparing mercapto-1,2,-triazines required asintermediates for preparation of compounds of the invention aredescribed below.

METHOD A

A general synthesis of 3-mercapto-1,2,4-triazines is by reaction betweenthiosemicarbazide and a 1,2 di-carbonyl compound. This is illustrated bythe preparation of 3-mercapto-5-methyl-1,2,4-triazine.

A solution of sodium bicarbonate (8 g) in water (100 cm³) was added to asuspension of thiosemicarbazide (8 g) in water (100 cm³). The resultingsolution was cooled below 5° C. and pyruvic aldehyde (40% weightsolution in water, (20 cm³)) was added. The solution was kept at 5° C.for 18 hours, then washed with chloroform (10×50 cm³). The pH of theaqueous layer was adjusted to 2 with concentrated hydrochloric acid. Theresulting precipitate was filtered off; washed with copious amounts ofwater and dried, giving an orange solid (4.036 g). The3-mercapto-5-methyl-1,2,4-triazine was used without further purificationin subsequent steps.

The following intermediate mercaptotriazines were prepared following theabove procedure. In some cases, ethanol was used as solvent in place ofwater. The starting materials were commercially available.

(i) 3-mercapto-1,2,4-triazine from glyoxal.

(ii) 3-mercapto-5-propyl-6methyl-1,2,4-triazine from hexane-2,3-dione. ¹H NMR: δ 0.98(3H,t); 1.54-1.68(2H,m); 2.08(3H,s); 3.04(2H,t); 8.2(1H,brs).

(iii) 3-mercapto-5-phenyl-6-methyl-1,2,4-triazine from1-phenylpropane-1,2-dione.

METHOD B

An alternative method for preparing mercapto-1,2,4-triazines comprisestreatment of a corresponding hydroxytriazine (which may exist in varioustautomeric forms) with a thiolating reagent such as phosphorouspentasulfide. This following illustrates the preparation of1,2,-triazine-3,5(2H,4H)-dithione from 1,2,4-triazine-3,5(2H,4H)-dione(6-azauracil).

6Azauracil (2 g), phosphorous pentasulfide (15.72 g) and pyridine 5 cm³were stirred together and heated under reflux for 56 hours. The reactionmixture was allowed to cool and most of the pyridine was removed byevaporation under reduced pressure. The residue was agitated withdiethyl ether and water and the organic layer was separate. The aqueouslayer was extracted with three further portions of diethyl ether and thecombined organic phases were washed with saturated aqueous brine, dried(MgSO₄) and evaporated under reduced pressure to give a brown oil whichwas chromatographed on silica gel, using 1:5 ethyl acetate:hexane aseluant. This gave an orange solid (1 g) which was used without furtherpurification. ¹ H NMR (DMSO-d₆): δ 7.95(1H,s); 13.8-14.1(1H,br s);14.3-14.6(1H,br s)

3-Mercapto-1,2,4-benzotriazine was prepared from3-hydroxy-1,2,4-benzotriazine and 6-methyl-1,2,3-triazine-5(4H)-thionefrom 6-methyl-1,2,3-triazine-5(4H)-one following essentially the aboveprocedure.

EXAMPLE XX.2

This Example illustrates the preparation of compounds according to theinvention which contain a 1,2,4-triazine substituted with a4,4-difluorobut-3-enylthio group in the 3, 5 or 6-position, startingfrom a correspondingly substituted mercaptotriazine and an appropriatedifluorobut-1-ene alkylating agent. This is demonstrated by thefollowing preparation of3-(4,4-difluorobut-3-enylthio)-5-hydroxy-1,2,4-triazine (CompoundXX.227) from 6-aza-2-thiouracil and 4,4-difluorobut-3-enyl4-methyl-benzenesulfonate.

4,4-Difluorobut-3-enyl 4-methyl-benzenesulfonate (1.5 g) and potassiumiodide (0.95 g) were stirred in ethanol (5 cm³) and heated under refluxfor three hours then allowed to cool. This part of the procedureconverts the starting material to the more chemically reactive andthio-selective alkylating agent, 4-iodo-1,1-difluorobut-1-ene.6Aza-2-thiouracil (0.744 g) was added as a solution in 1M aqueous sodiumhydroxide (5.73 cm³) and the reaction mixture stirred at ambienttemperature for 70 hours. The reaction was worked up by addition of anexcess of 1M aqueous sodium hydroxide and ethyl acetate. The ethylacetate layer was separated and the aqueous layer was washed with moreethyl acetate. These extracts were discarded The aqueous layer was thenacidified to pH4 with 2M aqueous hydrochloric acid. The product wasextracted into ethyl acetate (3 portions) and these combined organiclayers were washed with water and saturated aqueous brine and dried(MgSO₄). The product was recovered from the solution by evaporationunder reduced pressure to give a cream solid (0.659 g). A portion wasredissolved in hot ethyl acetate and some insoluble material removed byfiltration. Compound XX.227 recovered from solution by evaporation hadmp 102-103° C. M⁺ =219; ¹ H NMR (DMSO-d₆): δ 2.41(2H,m); 3.25(2H,t);4.55-4.75(1H,m); 7.69 and 7.79(total 1H,ea s, tautomeric protons)

Compound XX.247 was prepared using a related procedure, as follows.

6-Methyl-1,2,3-triazine-5(4H)-thione (0.5 g),4-bromo-1,1-difluorobut-1-ene (0.673 g) and potassium carbonate (0.543g) were stirred together in acetone (5 cm³) for 60 hours at the ambienttemperature. Then inorganic material was filtered off and washed withacetone. Solvent was removed from the combined acetone solutions byevaporation under reduced pressure and the residual brown gum waschromatographed on silica, eluting with 20% ethyl acetate in hexane, togive 5-(4,4-difluorobut-3-enylthio-6-methyl-1,2,4-triazine (CompoundXX.247) (0.075 g). M⁺ =217; ¹ H NMR: δ 2.45(2H,m); 2.60(3H,s);3.29(2H,t); 4.2-4.40(1H,m); 9.11(1H,s); (oil).

EXAMPLE XX.3

When the mercaptotriazine is fully soluble in acetone and carries noother potentially interfering nucleophilic groups a procedurealternative to that of Example XX.2 may be used

This is illustrated by the following preparation of3,5-bis-(4,4-difluorobut-3-enylthio)-1,2,4-triazine (Compound XX.231)from 1,2,4-triazine-3,5(2H,4H)-dithione and 4,4-difluoro-3-butenyl4-methyl-benzenesulfonate.

1,2,4-Triazine-3,5(2H,4H)-dithione (1 g), 4,4-difluorobut-3-enyl4-methyl-benesulfonate (3.6 g), potassium iodide (1.14 g) and potassiumcarbonate (0.952 g) were stirred and heated under reflux in acetone (20cm³) for 7 hours. The solution was cooled and filtered to remove solids.The filtrate and further acetone washings of the solids were combinedand evaporated under reduced pressure to give a brown oil.Chromatography on silica gel using 15:85 ethyl acetate:hexane as eluantgave Compound XX.231 (1 g) as an orange oil. M⁺ =325; ¹ H NMR: δ2.40-2.55(4H,m); 3.25(4H,m); 4.15-4.40(2H,m); 8.70(1H,s).

EXAMPLE XX.4

This Example illustrates a general procedure for the two-steppreparation of compounds according to the invention by reaction of amercapto-substituted 1,2,4-triazine with 4-bromo-4,4-difluorobutylmethanesulfonate followed by dehydrobromination of the resultingintermediate as demonstrated by the following preparation of3-(4,4-difluorobut-3-enylthio)-5-phenyl-6-methyl-1,2,4-triazine(Compound XX.4).

Step 1:3-(4-bromo-4,4-difluorobutylthio)-5-phenyl-6-methyl-1,2,4-triazine,

A mixture of 4-bromo-4,4-difluorobutyl methanesulfonate (0.7 g),3-mercapto-5-phenyl-6-methyl-1,2,4-triazine (0.5 g) and potassiumcarbonate (0.7 g) were sired together and heated under reflux in acetone(40 cm³) for 14 hours. Inorganic solids were removed by filtration andthe filtrate evaporated under reduced pressure to give a brown oil(1.058 g). Chromatography on silica gel using 1:4 ethyl acetate:hexaneas eluant gave an orange oil (0.576 g). This was stirred and heatedunder reflux in trifluoroacetic acid (3 cm³) for 6 hours to re-cyclisesome material which had undergone partial hydrolysis and ring opening.Product was recovered by evaporation of the solvent under reducedpressure and chromatography on silica gel and gave3-(4-bromo-4,4-difluorobutylthio)-5-phenyl-6-methyl-1,2,4triazine.(0.509 g). ¹ H NMR: δ 2.12-2.24(2H,m); 2.48-2.68(2H,m); 2.78(3H,s);3.36(2H,t); 7.50-7.58(3H,m); 7.68-7.74(2H,m); (oil).

Step 2: 3-(4,4-difluorobut-3-enylthio)-5-phenyl-6-methyl-1,2,4-triazine

1,8-Diazabicyclo 5.4.0! undec-7-ene (DBU) (1 cm³) was added dropwise toa stirred solution of the product from step 1 (0.5 g) in toluene (10cm³). The mixture was kept at ambient temperature for 20 hours, thenexcess ethyl acetate and saturated aqueous ammonium chloride were addedand the organic phase separated. The aqueous phase was extracted withethyl acetate and the combined organic phases were washed with saturatedaqueous ammonium chloride, dried (MgSO₄), filtered and evaporated underreduced pressure to give an orange oil (0.43 g). Chromatography onsilica gel using 1:4 ethyl acetate:hexane as eluant gave Compound XX.4(0.281 g). M⁺ =293; ¹ H NMR: δ 2.48-2.58(2H,m); 2.76 (3H,s); 3.32(2H,t);4.22-4.40(1H,m); 7.48-7.58(3H,m); 7.68-7.76(2H,m); (oil).

EXAMPLE XX.5

This Example illustrates a procedure suitable for the preparation ofcompounds according to the invention carrying an alkoxy, or substitutedalkoxy, group on the 5-position of the triazine ring from a compoundcarrying alkenylthio groups in both the 3 and 5-positions, asdemonstrated by the preparation of3-(4,4-difluorobut-3-enylthio)-5-methoxy-1,2,4-triazine (CompoundXX.221) from Compound XX.231.

Compound XX.231 (0.5 g) was stirred for one hour with sodium methoxide(0.083 g) in methanol (15 cm³) at ambient temperature. The solvent wasremoved by evaporation under reduced pressure and the residue waschromatographed on silica gel, eluting with 15:85 ethyl acetate:hexane,and gave 0.12 g of Compound XX.221. M⁺ =233; ¹ H NMR: δ 2.50(2H,m);3.29(2H,t); 4.02(3H,s); 4.22-4.42(1H,m); 8.55(1H,s) as a single isomerwhose identity as the 5-methoxy compound was confirmed by nmr.

The following compounds according to the invention were prepared usingthe above procedure with the appropriate alkoxide in the correspondingalcohol as solvent:

(i) 3-(4,4-difluorobut-3-enylthio)-5-(1-methyl-ethoxy)-1,2,4-triazine(Compound XX.205). M³⁰ =261; ¹ H NMR: δ 1.4(6H,d); 2.5(2H,m);3.25(2H,t); 4.2-4.4(1H,m); 5.4(1H,m); 8.45(1H,s).

(ii) 3-(4,4-difluorobut-3-enylthio)-5-ethoxy-1,2,4-triazine (CompoundXX.218). M⁺ =247; ¹ H NMR: δ 1.43(3H,t); 2.50(2H,m); 3.26(2H,t);4.2-4.4(1H,m); 4.46(2H,q); 8.5(1H,s)

EXAMPLE XX.6

This Example illustrates a 2-step procedure used for the preparation ofCompounds XX.52 and XX.116 as a 1:1 mixture.

Step 1: 3-(4-bromo-4,4-difluorobutylthio)-5-methyl-1,2,4-triazine and3-(4-bromo-4,4-difluorobutylthio)-6-methyl-1,2,4-triazine

4-bromo-4,4-difluorobutyl methanesulfonate (1 g) and thiosemicarbazide(0.475 g) were stirred together and heated under reflux in ethanol (20cm³) for 5 hours. GC indicated complete consumption of themethanesulfonate. The mixture was allowed to cool and water (3 cm³) andsodium bicarbonate (1 g) were added (effervescence). A 40% by weightsolution of pyruvic aldehyde (1 cm³) was then added and the mixturestirred at ambient temperature for 4 hours. TLC showed that product hadformed. It was extracted into ethyl acetate and the organic layer wasdried (MgSO₄), filtered and evaporated to give an oil (1.209 g). Thisintermediate product was purified by chromatography on silica gel,eluting with 1:4 ethyl acetate:hexane and gave a yellow oil (0.464 g)which had ¹ H NMR: δ 2.08-2.20(2H,m); 2.48-2.62(2H,m); 2.52 and 2.66(total 3H,ea s); 3.28-3.38(2H,m); 8.28 and 8.84 (total 1H, ea s),indicating it to be an approximately 1:1 mixture of the 5- and 6-methylisomers.

Step 2: 3-(4,4-difluorobut-3-enylthio)-5-methyl-1,2,4-triazine and3-(4,4-difluorobut-3-enylthio)-6-methyl-1,2,4-triazine

The mixture of products from Step 1 (0.46 g) were dehydrobrominatedusing DBU in a procedure analogous to Step 2 of Example XX.4 and theproduct (0.253 g) was purified by chromatography on silica gel elutingwith dichloromethane. Under these conditions the 5-and 6-methyl isomerswere inseparable and 0.232 g of a yellow oil was obtained which had M⁺=217; ¹ H NMR: δ 2.44-2.54(2H,m); 2.50 and 2.66 (total 3H,ea s);3.26-3.34(2H,m); 4.22-4.40(1H,m); 8.28 and 8.82 (total 1H, ea s); thisindicated it to be a 1:1 mixture of Compound XX.52 and Compound XX.116.

Compound XX.251 according to the invention was prepared using the aboveprocedure but taking cyclohexane-1,2-dione in Step 1 in place of pyruvicaldehyde. ¹ H NMR: δ 1.86-1.98(4H,m); 2.42-2.54(2H,m); 2.84-2.92(2H,m);3.04-3.12(2H,m); 3.28(2H,t); 4.22-4.38(1H,m); (oil).

EXAMPLE XX.7

This Example illustrates an alternative procedure used for thepreparation of Compounds XX.52 and XX.116 as a chromatographicallyseparable mixture.

4,4-difluorobut-3-enyl 4-methyl-benzenesulfonate (1 g) andthiosemicarbazide (0.4 g) were stirred together and heated under refluxin ethanol (20 cm³) for 6 hours. The mixture was allowed to coolovernight, whereupon a crystalline yellow precipitate of the S-alkylatedcompound was evident. This was not isolated but solvent was removed byevaporation at reduced pressure and the residue (1.3 g) was treated withsodium bicarbonate (0.928 g), water (3 cm³) and ethanol (20 cm³). A 40%by weight solution of pyruvic aldehyde (0.9 cm³) was then added (slighteffervescence) and the mixture stirred at ambient temperature for 1hour. The reaction was poured into water and the product was extractedinto ethyl acetate (3 portions). The combined organic phases were dried(MgSO₄), filtered and evaporated to give a brown gum (0.85 g).Chromatography on silica gel, eluting with 10% ethyl acetate in hexanegave a fraction which was identified as Compound XX.116 (0.05 g)(containing 10% of Compound XX.52 by NMR). Continued elution gave amixed fraction containing an approximately 1:1 mixture of CompoundsXX.52 and XX.116 (0.16 g) and then a fraction identified as CompoundXX.52 (0.1 g) (containing 15% of Compound XX.116 by NMR).

EXAMPLE XX.8

This Example illustrates a general procedure for the two-steppreparation of compounds according to the invention by reaction ofthiosemicarbazide with 4-bromo-1,1-difluorobut-1-ene and thencyclisation of the intermediate with a 1,2-dicarbonyl compound, asdemonstrated by the following preparation of3-(4,4difluorobut-3-enylthio)-1,2,4-triazine (Compound XX.137).

Thiosemicarbazide (2.6 g) was stirred with 4-bromo-1,1-difluorobut-1-enein ethanol (75 cm³) and the mixture heated under reflux for 7 hours andallowed to cool to the ambient temperature. Glyoxal (4.2 g of a 40%aqueous solution) and sodium hydrogen carbonate (7.37 g) were added andthe resulting mixture was stirred at the ambient temperature for 18hours. Water was added and the product was extracted into three portionsof ethyl acetate. The combined organic phases were washed with saturatedbrine, dried (MgSO₄), filtered and evaporated under reduced pressure togive a brown gum. Chromatography on silica gel, eluting with 20% ethylacetate in hexane gave Compound XX.137. M⁺ =203; ¹ H NMR: δ 2.50(2H,m);3.30(2H,t); 4.20-4.40(1H,m); 8.39(1H,d); 8.95(1H,d) (oil).

The following compounds according to the invention were prepared usingthe above procedure with the appropriate 1,2-dicarbonyl compound inplace of glyoxal:

(i) 3-(4,4-difluorobut-3-enylthio)-5-propyl-1,2,4-triazine (CompoundXX.27) from 2-oxo-pentanal. M⁺ =245; ^(H) NMR: δ 1.0(3H,t);1.7-1.85(2H,m); 2.45-2.55(2H,m); 2.6(2H,t); 3.3(2H,t); 4.2-4.4(1H,m);8.8(1H,s) (oil). This preparation also gave the isomeric CompoundXX.109; M⁺ =245; ¹ H NMR: δ 1.0(3H,t); 1.75-1.9(2H,m); 2.45-2.55(2H,m);2.9(2H,t); 3.3(2H,t); 4.2-4.4(1H,m); 8.25(1H,s) (oil), the latter fasterrunning isomer in the chromatography being approximately 8% of themixture which was produced.

(ii) 3-(4,4-difluorobut-3-enylthio)-5-ethyl-1,2,4-triazine (CompoundXX.30) from 2-oxo-butanal. M⁺ =231; ¹ H NMR: δ 1.3-1.4(3H,t);2.45-2.55(2H,m); 2.75-2.85(2H,q); 3.25-3.35(2H,t); 4.2-4.4(1H,m);8.85(1H,s) (oil). The isomeric Compound XX.110 was detected in thereaction mixture but was not isolated. However, it was the major productof the cyclisation when 1,1-diethoxy-butan-2-one was used in place of2-oxo-butanal. Initial imine formation in water followed by cyclisationin aqueous acetone catalysed with pyridinium tosylate gave CompoundXX.110. M⁺ =231; ¹ H NMR: δ 1.4(3H,t); 2.50(2H,m); 2.95(2H,q);3.3(2H,t); 4.2-4.4(1H,m); 8.29(1H,s) (oil).

(iii) 3-(4,4difluorobut-3-enylthio)-6methyl-1,2,4triazine-5(4H)-one(Compound XX.226) from pyruvic acid. M⁺ 233; ¹ H NMR (DMSO-d₆): δ2.05(3H,s); 2.30(2H,m); 3.12(2H,t); 4.4-4.6(1H,m) (gum).

The following compounds according to the invention were prepared usingthe above procedure with a 2,2-dichloro aldehyde in place of glyoxal:

(iv) 3-(4,4-difluorobut-3-enylthio)-5-(1-methyl-ethyl)-1,2,4triazine(Compound XX.15). M⁺ =245; ¹ H NMR: δ 1.32(6H,d); 2.50(2H,m); 3.0(1H,m);3.3(2H,t); 4.20-4.40(1H,m); 8.82(1H,s) (oil) and the chromatographicallyfaster-running isomer3-(4,4difluorobut-3-3-enylthio)-6-(1-methyl-ethyl)1,2,4-triazine(Compound XX.98). M⁺ =245; ¹ H NMR: δ 1.4(6H,d); 2.50(2H,m);3.18-3.35(3H,m); 4.20-4.40(1H,m); 8.30(1H,s) (oil) from2,2-dichloro-3-methyl-butanal.

EXAMPLE XX.9

This Example illustrates a preparation of5-dichloromethyl-3-(4,4-difluorobut-3-enylthio)-1,2,4-triazine (CompoundXX.65) from Compound XX.52.

Compound XX.52 (3.1 g) and N-chlorosuccinimide (2 g) were stirred andheated together under reflux in carbon tetrachloride (40 cm³) for 1hour. The mixture was allowed to cool and stirred at the ambienttemperature for 4 hours. Solvent was removed by evaporation underreduced pressure and the black tarry residue was suspended in diethylether (40 cm³) and passed through a bed of hi-flo filter aid. Insolublematerial was washed with further diethyl ether and the combinedsolutions were evaporated under reduced pressure. The residue waspurified by chromatography on silica, eluting with diethyl ether: hexane1:1 and the fractions containing product were evaporated under reducedpressure and further purified by preparative tlc, eluting with 30%diethyl ether in hexane to give Compound XX.65 (0.2 g). ¹ H NMR: δ2.50(2H,m); 3.3(2H,t); 4.20-4.40(1H,m); 6.50(1H,s); 9.37(1H,s); (oil).

EXAMPLE XX.10

This Example illustrates a preparation of3-(4,4difluorobut-3enylsulfonyl)-5-propyl-1,2,4triazine (Compound XX.28)from Compound XX.27.

Compound XX.27 (0.2 g) was stirred at 5° C. in dichloromethane (5 cm³)and 3-chloro perbenzoic acid (0.282 g, 2 equiv.) was added. Stirringcontinued for 18 hours at the ambient temperature. The reaction wasquenched by the addition of a saturated aqueous solution of sodiumbicarbonate and the product was extracted into dichloromethane. Theorganic phase was separated, washed with saturated brine and dried(MgSO₄). After filtration and concentration by evaporation under reducedpressure, there was obtained an oil which was purified by chromatographyon silica gel using 3:7 ethyl acetate:hexane as eluant to give CompoundXX.28 (0.187 g). M⁺ =277; ¹ H NMR: δ 1.0-1.1(3H,t); 1.8-1.95(2H,m);2.6-2.7(2H,m); 2.9-3.0(2H,t); 3.7-3.8(2H,t); 4.2-4.4(1H,m); 9.3(1H,s);(oil).

The following compounds according to the invention were prepared by theabove procedure, using 1.75 equivalents of oxidant:

(i) 3-(4,4difluorobut-3-enylsulfinyl)5-methyl-1,2,4-triazine (CompoundXX.53); M⁺ =233; ¹ H NMR: δ 2.35-2.7(2H,m); 2.75(3H,s); 3.2-3.4(2H,m);4.2-4.35(1H,m); 9.25(1H,s); (oil) and3-(4,4-difluorobut-3-enylsulfonyl)5-methyl-1,2,4-triazine (CompoundXX.54); MH⁺ =250; ¹ H NMR: δ 2.6-2.7(2H,m); 2.8(3H,s); 3.7-3.8(2H,t);4.254.4(1H,m); 9.35(1H,s); (oil) from Compound XX.52.

(ii) 3-(4,4-difluorobut-3-enylsulfinyl)-6-methyl- 1,2,4-triazine(Compound XX.117); MH⁺ =234; ¹ H NMR: δ 2.3-2.75(2H,m); 2.85(3H,s);3.2-3.4(2H,m); 4.15-4.3(1H,m); 8.7(1H,s); (oil) and3-(4,4-difluorobut-3-enylsulfonyl)-6-methyl-1,2,4-triazine (CompoundXX.118); MH⁺ =250; ¹ H NMR: δ 2.6-2.7(2H,m); 2.9(3H,s); 3.65-3.75(2H,t);4.2-4.4(1H,m); 8.75(1H,s); (oil) from Compound XX.116.

EXAMPLE XX.1

This Example illustrates a preparation of2-(4,4-difluorobut-3-enylthio)-1,3,5-triazine (Compound XXI.1).

(4,4-difluorobut-3-enyl)-thiourea (as its 4-methyl-benzenesulfonatesalt) (0.9 g) and 1,3,5-triazine (0.216 g) were heated together underreflux in ethanol (20 cm³) for 4 hours. The reaction mixture was cooledand the solvent was removed by evaporation to give a solid which wastriturated with hexane. The hexane-soluble material was recovered byevaporation under reduced pressure. This gave Compound XX.1 (0.4 g). M⁺=203; ¹ H NMR: δ 2.45(2H,m); 3.20(2H,t); 4.20-4.40(1H,m); 8.82(2H,s);(oil).

The compounds of formula (I) are nematicidal and can be used to controlnematodes in plants. Thus, in a further aspect of the present invention,there is provided a method of killing or controlling nematodes, whichcomprises applying a compound of formula (I) to the nematode.

The term "controlling" extends to non-lethal effects which result in theprevention of damage to the host plant and the limitation of nematodepopulation increase. The effects may be the result of chemical induceddisorientation immobilisation, or hatch prevention or induction. Thechemical treatment may also have deleterious effects on nematodedevelopment or reproduction.

The compounds of the present invention can be used against both plantparasitic nematodes and nematodes living freely in the soil.

Examples of plant-parasitic nematodes are: ectoparasites, for example,Xiphinema spp., Longidorus spp., and Trichodorus spp.; semi-parasites,for example, Tylenchulus spp.; migratory endoparasites, for example,Pratylenchus spp., Radopholus spp. and Scutellonema spp.; sedentaryparasites, for example, Heterodera spp., Globodera spp. and Meloidogynespp.; and stem and leaf endoparasites, for example, Ditylenchus spp.,Aphelenchoides spp. and Hirshmaniella spp.

The compounds of formula (I) also display activity against differenttypes of nematodes including cyst nematode.

The compounds of the present invention also exhibit activity againstother pests of growing and stored agronomic crops, forestry, greenhousecrops, ornamentals, nursery crops, stored food and fibre products. Thesepests include:

Heteroptera/Homoptera including Myzus persicae, Aphis gossypii, Aphisfabae, Rhopalosiphum padi, Aonidiella spp., Trialeurodes spp,. Bemisiatabaci, Nilaparvata lugens, Nephotettix cincticeps, Nezara viridula,Dysdercus suturellus, Dysdercus fasciatus, and Lygus lineoralis.

Diptera including Ceratitis capitata, Tipula spp., Oscinella fril,Liriomyza spp., Delia spp., and Peromya spp.

Lepidoptera including Pieris brassicae, Plutella xylostella, Spodopteralittoralis and other Spodoptera spp., Heliothis virescens and otherHeliothis and Helicoverpa spp., and Chilo partellus.

Coleoptera including Phaedon cochleariae, Diabrotica spp., Agrotis spp.,and Leptinotarsa decemlineata.

Blattodea including Blattella germanica Periplaneta americana, andBlatta orientalis.

Orthoptera including Chortiocetes terminifera, Schistocerca spp.,Locusta spp. and Scapteriscus spp.

Acari including Panonychus ulmi, Panoychus citri, Tetranychus urticae,Tetranychus cinnabarinus, Phyllocoptruta oleivora, and Brevipalpus spp.

The compounds can also be used against livestock, household, public andanimal health pests such as:

Siphonaptera including Ctenocephalides felis, Ctenocephalides canis,Xenopsylla cheopis, and Pulex irritans.

Mallophaga including Menopon gallinae, and Cuclotogaster heterographus.

Anoplura including Pediculus humanus capitis, Pediculus humanus humanus,and Phthirus pubis.

Diptera including Musca domestica, Aedes aegypti, Anopheles gambiae,Culex quinquefasciatus, Chrysops discalis, and Tabanus nigrovittatus.

Sarcophagidae including Sarcophaga haemorrhoidalis and Wohlfahrtiamagnifica.

Calliphoridae including Lucilia cuprina and Cordylobia anthropophaga.

Oestridae including Oestrus ovis.

Generally, the compounds may be used to combat and control pestsinjurious to and/or associated with the transmission of diseases of manand animals. The pests which may be combated and controlled by the useof the compounds of the invention parasitic nematodes of animals,including mammals, which may be found in the gastrointestinal te airpassages or blood vessels of the respiratory tract and the heart,together with the associated blood vessels.

The compounds of formula (I) may be used to treat vertebrates, such asmamals (for example, man, pigs, sheep, cattle, equines, cats and dogs),birds (for example, chicken, ducks, turkeys, geese, canaries andbudgerigars), and fish (for example, salmon, trout and ornamental fish).

The nematode and other pests may be killed/controlled by applying aneffective amount of one or more of the compounds of the presentinvention to the environment of the pests, to the area to be protected,as well as directly on the pests.

In order to apply the compound to the locus of the nematode, insect oracarid pest, or to a plant susceptible to attack by the nematode, insector acarid pest, the compound is usually formulated into a compositionwhich includes in addition to the compound of formula (I) suitable inertdiluent or carrier materials, and/or surface active agents. Thus in twofurther aspects of the invention there is provided a nematicidal,insecticidal or acaricidal composition comprising an effective amount ofa compound of formula (I) as defined herein and an inert diluent orcarrier material and optionally a surface active agent.

The amount of composition generally applied for the control of nematodepests gives a rate of active ingredient from 0.01 to 10 kg per hectare,preferably from 0.1 to 6 kg per hectare.

The compositions can be applied to the soil, plant, seed, or other areato be protected, to the locus of the pests, or to the habitat of thepests, in the form of dusting powders, wettable powders, granules (slowor fast release), emulsion or suspension concentrates, liquid solutions,emulsions, seed dressings, foggin/smoke formulations or controlledrelease compositions, such as microencapsulated granules or suspensions.

Dusting powders are formulated by mixing the active ingredient with oneor more finely divided solid carriers and/or diluents, for examplenatural clays, kaolin, pyrophyllite, bentonite, alumina,montmorillonite, kieselguhr, chalk, diatomaceous earths, calciumphosphates, calcium and magnesium carbonates, sulfur, lime, flours, talcand other organic and inorganic solid carriers.

Granules are formed either by absorbing the active ingredient in aporous granular material for example pumice, attapulgite clays, fuller'searth, kieselguhr, diatomaceous earths, ground corn cobs, and the like,or on to hard core materials such as sands, silicates, mineralcarbonates, sulfates, phosphates, or the like. Agents which are commonlyused to aid in impregnation, binding or coating the solid carriersinclude aliphatic and aromatic petroleum solvents, alcohols, polyvinylacetates, polyvinyl alcohols, ethers, ketones, esters, dextrins, sugarsand vegetable oils with the active ingredient. Other additives may alsobe included, such as emulsifying agents, wetting agents or dispersingagents.

Microencapsulated formulations (microcapsule suspensions CS) or othercontrolled release formulations may also be used, particularly for slowrelease over a period of time, and for seed treatment.

Alternatively the compositions may be in the form of liquid preparationsto be used as dips, irrigation additives or sprays, which are generallyaqueous dispersions or emulsions of the active ingredient in thepresence of one or more known wetting agents, dispersing agents oremulsifying agents (surface active agents). The compositions which areto be used in the form of aqueous dispersions or emulsions are generallysupplied in the form of an emulsifiable concentrate (EC) or a suspensionconcentrate (SC) containing a high proportion of the active ingredientor ingredients. An EC is a homogeneous liquid composition, usuallycontaining the active ingredient dissolved in a substantiallynon-volatile organic solvent. An SC is a fine particle size dispersionof solid active ingredient in water. To apply the concentrates they arediluted in water and are usually applied by means of a spray to the areato be treated For agricultural or horticultural purposes, an aqueouspreparation containing between 0.0001% and 0.1% by weight of the activeingredient (approximately equivalent to from 5-2000 g/ha) isparticularly useful.

Suitable liquid solvents for ECs include methyl ketone, methyl isobutylketone, cyclohexanone, xylenes, toluene. chiorobenzene, paraffins,kerosene, white oil, alcohols, (for example, butanol),methylnaphthalene, trimethylbenzene, trichloroethylene,N-methyl-2-pyrrolidone and tetrahydrofurfuryl alcohol (THFA).

Wetting agents, dispersing agents and emulsifying agents may be of thecationic, anionic or non-ionic type. Suitable agents of the cationictype include, for example, quaternary ammonium compounds, for examplecetyltrimethyl ammonium bromide. Suitable agents of the anionic typeinclude, for example, soaps, salts of aliphatic monoesters of sulfuricacid, for example sodium lauryl sulfate, salts of sulfonated aromaticcompounds, for example sodium dodecylbenzenesulfonate, sodium, calciumor ammonium lignosulfonate, or butylnaphthalene sulfonate, and a mixtureof the sodium salts of diisopropyl- and triisopropylnaphthalenesulfonates. Suitable agents of the non-ionic type include, for example,the condensation products of ethylene oxide with fatty alcohols such asoleyl alcohol or cetyl alcohol, or with alkyl phenols such as octylphenol, nonyl phenol and octyl cresol. Other non-ionic agents are thepartial esters derived from long chain fatty acids and hexitolanhydrides, the condensation products of the said partial esters withethylene oxide, and the lecithins.

These concentrates are often required to withstand storage for prolongedperiods and after such storage, to be capable of dilution with water toform aqueous preparations which remain homogeneous for a sufficient timeto enable them to be applied by conventional spray equipment. Theconcentrates may contain 1-85% by weight of the active ingredient oringredients. When diluted to form aqueous preparations such preparationsmay contain varying amounts of the active ingredient depending upon thepurpose for which they are to be used.

The compounds of formula (I) may also be formulated as powders (dry seedtreatment DS or water dispersible powder WS) or liquids (flowableconcentrate FS, liquid seed treatment LS), or microcapsule suspensionsCS for use in seed treatments. The formulations can be applied to theseed by standard techniques and through conventional seed treaters. Inuse the compositions are applied to the nematodes, to the locus of thenematodes, to the habitat of the nematodes, or to growing plants liableto infestation by the nematodes, by any of the known means of applyingpesticidal compositions, for example, by dusting, spraying, orincorporation of granules.

The compounds of the invention may be the sole active ingredient of thecomposition or they may be admixed with one or more additional activeingredients such as nematicides or agents which modify the behaviour ofnematodes such as hatching factors, insecticides, synergists,herbicides, fungicides or plant growth regulators where appropriate.

Suitable additional active ingredients for inclusion in admixture withthe compounds of the invention may be compounds which will broaden thespectrum of activity of the compounds of the invention or increase theirpersistence in the location of the pest. They may synergise the activityof the compound of the invention or complement the activity for exampleby increasing the speed of effect or overcoming repellency. Additionallymulti-component mixtures of this type may help to overcome or preventthe development of resistance to individual components.

The particular additional active ingredient included will depend uponthe intended utility of the mixture and the type of complementary actionrequired. Examples of suitable insecticides include the following:

a) Pyrethroids such as permethrin, esfenvalerate, deltamethrin,cyhalothrin in particular lambda-cyhalothrin, bifenthrin, fenpropathrin,cyfluthrin, tefluthrin, fish safe pyrethroids for example ethofenprox,natural pyrethrin, tetamethrin, s-bioallethrin, fenfluthrin, prallethrinand5-benzyl-3-furylmethyl-(E)-(1R,3S)-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropane carboxylate;

b) Organophosphates such as profenofos, sulprofos, methyl parathion,azinphos-methyl, demeton-s-methyl, heptenophos, thiometon, fenamiphos,monocrotophos, triazophos, methamidophos, dimethoate, phosphamidon,malathion, chloropyrifos, phosalone, terbufos, fensulfothion, fonofos,phorate, phoxim, pyrimiphos-methyl, pyrimiphos-ethyl, fenitrothion ordiazinon;

c) Carbamates (including aryl carbamates) such as pirimicarb,cloethocarb, carbofuran, furathiocarb, ethiofencarb, aldicarb,thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur or oxamyl;

d) Benzoyl ureas such as tiflumuron. or chlorofluazuron;

e) Organic tin compounds such as cyhexatin, fenbutatin oxide,azocyclotin;

f) Macrolides such as avermectins or milbemycins, for example such asabamectin, ivermectin and milbemycin;

g) Hormones and pheromones;

h) Organochlorine compounds such as benzene hexachloride, DDT,endosulphan, chlordane or dieldrin;

i) Amidines, such as chlordimeform or amitraz

j) Fumigant agents;

k) Nitromethylenes such as imidacloprid.

In addition to the major chemical classes of insecticide listed above,other insecticides having particular targets may be employed in themixture if appropriate for the intended utility of the mixture. Forinstance selective insecticides for particular crops, for examplestemborer specific insecticides for use in rice such as cartap orbuprofezin can be employed. Alternatively insecticides specific forparticular insect species/stages for example ovo-larvicides such asclofentezine, flubenzimine, hexythiazox and tetradifon, motilicides suchas dicofol or propargite, general acaricides such as bromopropylate,chlorobenzilate, or growth regulators such as hydramethylnon,cyromazine, methoprene, chlorfluazuron and diflubenzuron may also beincluded in the compositions.

Examples of suitable synergists for use in the compositions includepiperonyl butoxide, sesamax, safroxan and dodecyl imidazole.

Suitable herbicides, fungicides and plant-growth regulators forinclusion in the compositions will depend upon the intended target andthe effect required.

An example of a rice selective herbicides which can be included ispropanil, an example of a plant growth regulator for use in cotton is"Pix", and examples of fungicides for use in rice include blasticidessuch as blasticidin-S. The ratio of the compound of the invention to theother active ingredient in the composition will depend upon a number offactors including type of target, effect required from the mixture etc.However in general, the additional active ingredient of the compositionwill be applied at about the rate as it is usually employed or at aslightly lower rate if synergism occurs.

EXAMPLE 1

The activity of compounds of formula (I) according to the invention wasdetermined using a variety of pests. The pests were treated with aliquid composition containing 500 parts per million (ppm) by weight ofthe compound unless otherwise stated. The compositions were made bydissolving the compound in acetone: ethanol (50:50) mixture and dilutingthe solutions with water containing 0.05% by weight of a wetting agentsold under the trade name "Synperonic" NP8 until the liquid compositioncontained the required concentration of the compound. "Synperonic" is aRegistered Trade Mark

The test procedure adopted with regard to each pest was basically thesame and comprised supporting a number of the pests on a medium whichwas usually a host plant or a foodstuff on which the pests feed, andtreating either or both the medium and the pests with the compositions.The mortality of the pests was then assessed at periods usually varyingfrom one to three days after the treatment.

The results of the tests are presented in Table A for each of thecompounds. The results indicate a grading of mortality designated as A,B or C wherein A indicates less than 40% mortality, B indicates 40-79%mortality and C indicates 80-100% mortality;--indicates that either thecompound was not tested or no meaningful result was obtained

Information regarding the pest species, the support medium or food, andthe type and duration of the test is given in Table B. The pest speciesis designated by a letter code.

                  TABLE A    ______________________________________    Compound   SPECIES (see Table B)    No.        TU    MPa       MD   HV     SE  DB    ______________________________________    II.1       B     A         A    A      A   --    II.2       C     C         A    A      A   --    II.3       A     A         A    A      A   --    II.4       A     A         A    A      A   --    II.5       A     C         A    A      A   --    II.6       C     A         A    A      A   --    II.7       A     A         A    B      A   --    II.8       C     C         A    C      B   --    II.9       B     C         A    A      A   --    III.1      A     C         A    A      A   B    III.2      C     C         A    C      A   --    III.3      A     C         A    A      A   --    III.4      A     A         A    A      A   --    III.5      A     A         A    A      A   --    III.6      A     A         A    C      A   --    III.7      A     A         A    B      A   --    III.8      A     A         A    A      A   --    III.9      B     C         A    A      A   --    III.10     A     C         A    B      A   --    III.11     A     A         A    A      A   --    III.12     B     A         A    A      A   --    IV.1       C     C         A    C      B   C    IV.2       C     C         A    C      B   C    IV.3       C     C         A    B      A   B    IV.7       C     C         A    C      A   --    IV.8       C     C         A    C      A   --    IV.9       C     C         A    C      A   --    IV.10      C     C         --   B      A   --    IV.23      C     C         A    C      B   --    IV.24      C     C         A    A      A   --    IV.26      C     C         A    A      A   --    V.2        C     C         A    C      C   --    V.12       C     C         A    C      A   --    V.15       C     C         A    A      A   --    VI.1       A     C         A    A      A   --    VI.4       A     A         A    A      A   --    VI.5       C     C         A    A      A   --    VI.6       C     A         A    A      A   --    VI.13      B     C         --   A      A   --    VI.14      C     C         --   A      A   --    VI.15      A     C         --   A      A   --    VI.16      C     C         --   B      A   --    VI.18      C     C         A    B      A   C    VI.19      C     C         B    B      A   A    VI.20      C     C         A    A      A   C    VI.25      C     C         A    B      A   --    VI.31      C     C         A    A      A   --    VI.32      C     C         A    A      A   --    VI.36      C     A         A    A      A   --    VI.37      C     C         A    A      A   --    VI.38      C     C         A    A      A   --    VI.40      C     C         A    C      A   --    VII.1      C     C         B    A      A   B    VII.2      C     C         A    C      B   --    VII.3      C     A         A    B      A   --    VII.4      A     B         A    A      A   --    VII.6      C     C         A    B      A   --    VII.7      C     C         A    C      A   --    VII.8      C     C         A    A      A   --    VII.9      C     C         A    B      A   --    VII.10     C     B         A    B      A   --    VII.11     C     C         A    B      A   --    VII.13     C     C         A    B      A   --    VII.14     C     C         A    A      A   --    VII.15     C     C         A    B      A   --    VII.16     C     C         A    A      A   --    VII.17     C     C         A    A      A   C    VII.21     B     C         A    A      A   --    VII.23     A     B         A    A      A   --    VII.24     A     C         A    A      A   --    VII.25     C     C         A    C      A   --    VII.26     C     C         A    B      A   --    VII.27     C     C         --   A      A   --    VII.28     C     C         --   A      A   --    VII.32     C     C         A    C      A   --    VII.36     C     C         A    B      A   --    VII.41     C     C         A    C      A   --    VII.43     C     C         A    B      A   --    VII.45     C     C         A    C      A   --    VII.47     C     C         A    C      A   --    VII.52     C     C         A    A      B   --    VII.53     C     C         A    A      A   --    VII.56     C     C         A    C      A   --    VII.82     C     C         A    B      A   --    VII.83     A     C         --   C      A   --    VII.84     A     C         --   A      A   --    VII.90     C     C         A    B      A   --    VII.94     C     C         A    C      A   --    VII.98     C     C         A    C      A   --    VII.102    A     A         A    A      A   --    VII.114    C     A         A    A      A   --    VII.115    A     C         A    A      A   --    VII.116    B     A         A    A      A   --    VII.128    C     C         A    A      A   --    VII.130    C     C         --   A      A   --    VII.134    A     A         A    C      A   A    VIII.1     C     C         A    B      A   --    VIII.2     A     C         A    A      A   --    VIII.3     C     C         A    B      A   --    VIII.4     A     A         A    A      C   --    VIII.5     C     C         A    C      A   C    VIII.7     C     C         A    A      A   --    VIII.8     C     A         A    A      A   --    VIII.9     A     A         A    A      A   --    VIII.10    C     C         A    A      A   --    VIII.11    C     C         A    B      A   --    VIII.12    C     C         A    B      A   --    VIII.13    A     C         A    A      A   --    VIII.14    C     C         A    A      A   --    VIII.15    C     B         A    A      A   --    VIII.18    C     C         A    A      A   --    VIII.19    C     C         A    A      A   --    VIII.20    C     C         A    A      A   --    VIII.21    A     A         A    A      A   --    VIII.22    C     C         A    A      A   --    VIII.23    C     C         A    A      C   --    VIII.24    C     C         A    A      B   --    VIII.27    C     C         A    B      A   --    VIII.28    A     C         A    A      A   --    VIII.29    C     C         A    C      A   --    VIII.30    A     C         A    A      A   --    VIII.31    C     C         A    A      A   --    VIII.32    B     C         A    A      A   --    VIII.33    C     C         A    A      A   --    VIII.34    B     B         A    A      A   --    VIII.36    C     C         A    A      A   --    VIII.52    A     C         --   A      A   --    VIII.53    A     C         A    A      A   --    VIII.58    C     C         A    C      A   --    VIII.59    C     C         A    A      A   --    VIII.61    C     C         A    A      A   --    VIII.63    A     A         A    A      C   --    VIII.64    C     C         A    A      A   --    VIII.65    A     B         --   A      A   --    VIII.66    A     A         A    A      A   --    VIII.67    A     A         A    A      A   --    VIII.68    C     C         A    A      A   --    VIII.151   C     C         A    B      A   --    VIII.152   C     C         --   A      A   --    IX.31      C     C         A    A      A   --    IX.33      A     A         A    A      A   --    IX.34      B     C         A    A      A   --    IX.36      A     C         A    A      A   --    IX.37      C     C         A    A      B   --    IX.40      A     A         A    A      A   --    IX.42      A     A         A    A      A   --    IX.55      C     A         A    A      A   --    IX.61      A     C         A    A      A   --    IX.73      C     C         A    A      C   --    IX.75      C     C         A    A      A   --    IX.82      C     C         A    C      B   --    IX.84      C     A         A    C      A   --    IX.124     C     A         A    A      A   --    IX.126     A     A         A    A      A   --    X.3        C     C         A    C      C   --    X.26       C     C         A    C      A   --    X.32       C     A         A    A      A   --    XI.5       C     C         A    C      C   C    XI.9       A     A         A    A      A   --    XI.11      C     C         A    C      A   --    XI.23      C     C         A    C      A   --    XI.24      A     C         A    A      A   --    XI.25      C     C         A    B      A   --    XI.30      A     C         A    A      A   --    XI.31      A     C         A    A      A   --    XI.34      C     C         A    B      A   --    XI.35      C     C         A    C      A   --    XI.36      C     C         A    C      A   --    XI.38      C     C         A    C      A   --    XI.40      C     C         A    A      A   C    XI.87      C     C         A    C      A   --    XI.102     B     C         A    A      A   --    XI.108     B     C         A    B      A   --    XI.109     C     A         A    C      B   --    XI.110     C     C         A    B      A   --    XI.125     C     C         A    C      A   --    XI.127     C     C         A    B      B   B    XII.1      C     C         A    C      B   --    XII.3      C     C         A    C      C   B    XII.4      C     C         A    B      A   C    XII.5      C     C         A    A      A   B    XII.8      C     C         A    A      A   --    XII.9      A     B         A    B      A   --    XII.11     C     C         A    B      A   --    XII.12     C     C         A    B      A   --    XII.13     C     C         A    B      A   --    XII.14     C     C         A    C      A   --    XII.15     C     C         A    A      A   --    XII.19     C     C         A    A      B   --    XII.23     C     C         A    C      A   --    XII.25     C     C         A    C      A   --    XII.26     C     C         A    B      A   --    XII.27     C     C         A    A      A   --    XII.28     C     C         A    C      A   --    XII.29     C     C         A    C      A   --    XII.30     C     C         A    B      A   --    XII.31     C     C         A    A      A   --    XII.32     C     C         A    C      A   --    XII.33     C     C         A    C      A   --    XII.35     C     C         A    A      A   --    XII.49     C     C         A    C      A   --    XII.51     C     C         A    C      A   --    XII.54     C     C         A    C      A   --    XII.55     C     A         A    C      A   --    XII.68     C     A         A    A      A   --    XII.128    C     C         A    B      C   --    XII.129    C     C         A    C      A   --    XII.130    C     C         A    A      A   --    XII.131    C     C         A    C      A   --    XII.132    C     C         A    B      C   --    XII.133    C     C         A    A      A   --    XII.134    C     C         A    C      B   --    XII.142    C     C         A    C      A   --    XII.143    C     B         A    A      A   --    XII.144    C     C         A    B      A   --    XII.145    C     C         A    C      A   --    XII.146    B     C         A    A      A   --    XII.147    C     C         A    A      A   --    XII.148    C     C         A    C      A   --    XIII.1     C     A         A    B      A   --    XIII.2     C     C         A    C      A   --    XIII.3     C     C         A    B      A   --    XIII.4     C     C         A    A      A   --    XIII.6     C     A         A    C      A   --    XIII.7     C     C         A    C      A   --    XIII.9     C     C         A    C      A   --    XIII.10    C     C         A    B      A   --    XIII.11    C     C         A    A      A   --    XIII.14    A     A         A    A      A   --    XIII.15    C     C         A    A      A   --    XIII.16    C     A         A    B      A   --    XIII.17    C     C         A    C      A   --    XIII.18    C     C         A    B      A   --    XIII.20    C     C         A    B      A   --    XIII.24    C     C         A    B      A   --    XIII.27    C     A         A    C      A   --    XIII.28    C     C         A    B      A   --    XIII.29    C     C         A    B      A   --    XIII.40    C     C         A    C      A   B    XIII.41    C     C         A    C      A   --    XIII.42    C     C         A    C      A   --    XIII.45    C     C         A    A      A   --    XIII.63    A     A         A    A      A   B    XIII.64    C     C         A    C      A   --    XIII.65    C     C         A    C      A   --    XIII.66    C     C         A    B      A   --    XIII.69    C     B         A    B      A   --    XIII.70    A     C         A    B      A   A    XIII.101   C     C         A    A      A   --    XIII.110   C     C         A    C      A   C    XIII.114   C     C         A    C      A   --    XIII.115   C     C         A    C      A   --    XIII.116   A     C         A    C      A   --    XIII.117   C     C         B    A      B   B    XIII.119   B     C         C    C      A   C    XIII.122   C     C         A    A      A   --    XIII.124   C     C         B    B      A   B    XIII.133   C     C         A    C      A   C    XIII.134   C     C         A    B      A   B    XIII.143   C     A         A    C      A   --    XIV.1      C     C         A    C      A   C    XV.1       C     C         A    C      C   C    XVI.1      A     C         A    C      B   --    XVI.2      A     A         A    A      A   --    XVI.3      C     A         A    C      A   --    XVI.5      C     C         A    C      B   --    XVI.6      C     C         A    C      A   --    XVI.7      A     A         A    A      A   --    XVI.8      C     C         A    C      A   --    XVI.9      C     B         A    A      A   --    XVI.10     C     C         A    C      B   C    XVI.11     A     B         A    A      A   A    XVI.12     C     C         A    A      C   --    XVI.13     A     A         A    A      A   --    XVI.14     A     A         A    A      A   --    XVI.15     B     C         A    A      A   --    XVI.16     C     C         A    A      A   --    XVI.17     C     C         A    A      A   --    XVI.18     C     C         A    A      A   --    XVI.19     C     A         A    A      A   B    XVI.20     A     A         A    A      A   --    XVI.21     C     C         A    C      A   --    XVI.22     C     A         A    B      A   --    XVI.23     A     A         A    B      A   --    XVI.24     C     C         A    B      A   --    XVII.1     C     C         A    A      A   C    XVII.2     C     C         A    A      A   C    XVII.3     B     B         C    C      C   C    XVII.4     C     C         A    A      A   B    XVII.5     C     C         A    A      A   B    XVII.6     A     A         A    A      A   A    XVII.7     C     C         A    A      A   C    XVIII.1    C     C         A    C      A   C    XVIII.3    A     C         B    A      A   C    XVIII.4    C     C         A    A      C   C    XVIII.7    A     A         A    A      A   C    XVIII.10   C     C         A    B      A   --    XVIII.13   C     C         A    C      C   --    XVIII.14   C     C         A    A      A   --    XVIII.15   C     C         A    B      A   --    XVIII.16   C     C         A    B      B   --    XIX.1      C     C         B    C      A   C    XX.4       C     B         A    C      A   C    XX.15      C     A         A    A      A   --    XX.27      C     C         A    B      A   --    XX.28      C     C         A    A      B   --    XX.30      C     C         A    A      A   --    XX.52      C     C         A    B      A   --    XX.53      C     C         A    C      A   --    XX.54      C     C         A    B      A   --    XX.65      C     C         A    A      A   --    XX.98      C     C         A    A      A   --    XX.109     C     C         A    C      A   --    XX.110     C     C         A    A      A   --    XX.116     C     C         A    B      A   --    XX.117     C     C         A    C      A   --    XX.118     C     C         A    C      A   --    XX.137     C     C         A    B      A   --    XX.205     C     C         A    C      A   --    XX.218     C     C         A    C      A   --    XX.221     C     C         A    C      A   --    XX.226     C     A         A    C      C   --    XX.227     C     C         B    A      A   A    XX.231     C     C         A    C      A   --    XX.247     C     C         A    C      A   --    XX.251     C     C         A    A      A   B    XXI.1      C     C         B    A      A   A    ______________________________________

                  TABLE B    ______________________________________                        SUPPORT    CODE                MEDIUM/   TYPE OF                                         DURATION    LETTERS           TEST SPECIES FOOD      TEST   (days)    ______________________________________    TU     Tetranychus urticae                        French bean                                  Contact                                         3           (spider mite)                        leaf    MPa    Myzus persicae                        Chinese   Contact                                         3           (green peach aphid)                        Cabbage leaf    MD     Musca domestica                        Cotton wool/                                  Contact                                         2           (houseflies - adults)                        sugar    HV     Heliothis virescens                        Soya leaf Residual                                         5           (Tobacco bud-           worm - larva)    SE     Spodoptera exigua                        Cotton leaf                                  Residual                                         5           (lesser armyworm -           larva)    DB     Diabrotica balteata                        Filter paper/                                  Residual                                         2           (banded cucumber                        maize seed           beetle - larva)    ______________________________________

"Contact" test indicates that both pests and medium were treated, and"Residual" indicates that the medium was treated before infestation withthe pests.

EXAMPLE 2

This Example further illustrates the pesticidal activity of compounds offormula (I) according to the invention.

In Table C, further results are given for the activity of test compoundsagainst four species, at various rates of application. The testprocedures and details for tests TU (Tetranychus urticae, contact), MPa(Myzus persicae, contact) and DB (Diabrotica balteata, contact) are asdescribed in Example 1 and Table B. Application rates are shown in theTable heading for each test type. The test procedure for test MPb (Myzuspersicae, systemic) was as follows:

Upward systemicity of the test compounds was evaluated against the peachpotato aphid, Myzus persicae by soil drenching 2-3 week old radishplants (cv. Cherrybelle) at 10 ppm or 2.5 ppm. Plants with 1st trueleaves approximately 2×1 cm were used. The cotyledons, growing point and1 true leaf were removed. The soil was covered with a clear lid. 12-18mature aphids were added to each plant 1 day before treatment. On thetreatment day, each pot was placed in a 250 cm³ plastic pot with a fluonband to prevent aphid escape. Each pot was treated with 10 cm³ ofchemical in aqueous solution prepared in 1% ethanol and acetone (1:1)and 0.01% Synperonic NP8--ICI Chemicals and Polymers). Each treatmentwas replicated 3 times. The treated plants were transferred to aconstant environment room at 20° C., 60% relative humidity and a 16 hourphotoperiod. The mortality was assessed at 3 and 5 days after treatment.

Activity against the root knot nematode, Meloidogyne incognita (MI), wasevaluated by applying the candidate nematicide as a drench solution to 2week old cucumber plants (cultivar Telegraph) and infesting the soilwith nematodes. 10 cm³ of an aqueous solution of the test compound,(prepared in 1% ethanol and acetone (1:1) and 0.05% Synperonic NP8--ICIChemicals & Polymers) was added to each plant such that the final soilconcentration was 2 ppm. Each treatment was replicated twice. Thecucumber plants were inoculated 48 hours after treatment with a 2 cm³suspension of freshly hatched juveniles at a concentration of 350nematodes per cm³. The test was maintained at 25° C. with a 16 hourphotoperiod for 9 days. The roots of each plant were assessed forpercentage root-knot reduction relative to an untreated, infestedcontrol and the results are recorded in Table C as % knot reductioncompared to the control.

The results in Table C for the four species other than MI are expresedas % Control observed. A dash indicates that either the compound was nottested or that no meaningful result was obtained.

                                      TABLE C    __________________________________________________________________________    Compound          TU     MPa    MPa    MPb    MPb    DB     MI    No.   100 ppm                 100 ppm                        27  ppm                               10  ppm                                      2.5 ppm                                             25  ppm                                                    2   ppm    __________________________________________________________________________    II.1  --     --     --     --     1      --     95    II.2  88     --     --     --     100    --     100    II.3  --     --     --     --     --     --     0    II.4  --     --     --     --     4      --     96    II.5  --     --     --     --     --     --     96    II.6  39     --     --     --     --     --     88    II.7  --     --     --     --     4      --     98    II.8  74     --     24     --     100    --     97    II.9  --     --     58     --     100    --     98    III.1 --     --     5      --     --     --     98    III.2 60     --     58     --     97     --     93    III.3 --     --     8      --     41     --     83    III.4 --     --     --     --     --     --     0    III.5 --     --     --     --     --     --     30    III.6 --     --     --     --     --     --     47    III.7 --     --     --     --     --     --     48    III.8 --     --     --     --     --     --     0    III.9 --     7      --     --     --     --     88    III.10          --     8      --     --     --     --     51    III.11          --     --     --     --     --     --     0    III.12          --     --     --     --     --     --     0    IV.1  100    --     66     92     --     80     0    IV.2  94     --     82     84     --     17     0    IV.3  60     --     8      100    --     --     96    IV.7  100    100    --     --     100    --     100    IV.8  92     --     81     --     23     --     0    IV.9  93     --     81     --     50     --     0    IV.10 --     --     --     --     --     --     11    IV.23 --     --     --     97     --     --     99    IV.24 --     --     --     --     --     --     88    V.2   100    --     84     --     55     --     0    V.6   --     --     --     --     --     --     72    V.12  100    --     100    --     10     --     0    V.15  49     --     50     --     100    --     92    VI.1  --     --     2      --     --     --     99    VI.4  --     --     --     --     5      --     98    VI.5  84     95     --     --     100    --     100    VI.6  --     --     --     97     --     --     77    VI.13 --     --     --     --     --     --     22    VI.14 --     --     --     --     --     --     0    VI.15 --     --     --     --     --     --     72    VI.16 --     --     --     --     --     --     55    VI.18 73     --     65     60     --     100    95    VI.19 74     --     100    99     --     --     100    VI.20 97     --     100    95     97     53     98    VI.25 77     --     15     --     46     --     88    VI.32 28     --     12     --     28     --     100    VI.36 --     --     --     79     --     --     17    VI.37 93     --     100    --     86     --     97    VI.40 92     --     98     --     100    --     92    VII.1 38     --     0      --     51     --     99    VII.2 36     --     39     --     100    --     99    VII.3 45     --     --     --     --     --     0    VII.4 --     --     7      --     --     --     0    VII.6 100    --     98     --     65     --     95    VII.7 99     --     100    --     45     --     98    VII.8 46     --     16     --     4      --     86    VII.9 90     6      --     --     --     --     0    VII.10          37     7      --     --     --     --     0    VII.12          --     --     --     96     --     --     0    VII.14          --     --     --     --     --     --     91    VII.15          --     --     --     --     --     --     100    VII.16          88     100    --     --     96     --     100    VII.17          90     --     9      --     --     60     0    VII.22          --     --     --     --     --     --     76    VII.23          --     --     --     --     --     --     68    VII.24          --     --     17     --     50     --     98    VII.25          --     --     --     --     98     --     99    VII.26          95     --     30     --     96     --     100    VII.27          --     --     --     --     --     --     83    VII.28          --     --     --     --     --     --     66    VII.32          99     --     79     --     49     --     97    VII.36          100    --     100    --     90     --     92    VII.41          100    --     100    --     49     --     96    VII.43          85     100    --     --     --     --     86    VII.45          100    99     --     --     --     --     95    VII.47          --     --     --     --     --     --     94    VII.52          --     --     --     41     --     --     94    VII.53          --     --     --     67     --     --     99    VII.56          --     --     --     56     --     --     --    VII.83          --     --     --     --     --     --     66    VII.84          --     --     --     --     --     --     0    VII.90          97     --     92     --     93     --     95    VII.94          72     --     5      --     --     --     0    VII.98          56     --     11     --     --     --     0    VII.102          --     --     --     --     --     --     0    VII.114          --     --     --     28     --     --     50    VII.115          --     --     --     --     --     --     50    VII.116          --     --     --     --     --     --     33    VII.128          --     --     --     44     --     --     66    VII.130          --     --     --     --     --     --     28    VII.134          --     --     --     --     --     --     100    VIII.1          100    100    --     --     100    --     98    VIII.2          --     93     --     --     98     --     99    VIII.3          --     --     --     --     --     --     88    VIII.4          --     --     --     18     --     --     39    VIII.5          45     --     26     --     96     87     98    VIII.7          43     90     --     --     90     --     100    VIII.8          --     --     --     --     --     --     59    VIII.9          --     --     --     --     --     --     65    VIII.10          --     --     --     42     --     --     39    VIII.12          --     --     --     --     --     --     48    VIII.13          --     4      --     --     --     --     86    VIII.14          --     --     --     --     --     --     90    VIII.15          --     --     --     --     --     --     97    VIII.18          97     100    --     --     --     --     94    VIII.19          --     --     --     --     --     --     66    VIII.20          --     --     --     4      --     --     0    VIII.21          --     --     --     --     --     --     0    VIII.22          --     --     --     --     --     --     72    VIII.23          --     --     --     76     --     --     44    VIII.24          --     --     --     0      --     --     50    VIII.27          --     --     --     0      --     --     0    VIII.29          --     --     --     --     --     --     11    VIII.30          --     --     --     29     --     --     44    VIII.31          --     --     --     --     --     --     49    VIII.32          --     --     --     --     --     --     99    VIII.33          --     --     --     --     --     --     0    VIII.34          --     --     --     --     --     --     22    VIII.36          --     --     --     --     --     --     66    VIII.52          --     --     --     --     --     --     22    VIII.59          --     --     --     --     --     --     65    VIII.61          --     --     --     --     --     --     66    VIII.63          --     --     --     --     --     --     99    VIII.64          --     --     --     29     --     --     0    VIII.65          --     --     --     48     --     --     72    VIII.66          --     --     --     16     --     --     --    VIII.67          --     --     --     --     --     --     0    VIII.151          100    100    --     --     30     --     99    VIII.152          --     --     --     --     --     --     33    IX.33 --     --     --     0      --     --     44    IX.34 --     --     --     0      --     --     94    IX.36 --     --     --     2      --     --     0    IX.37 --     --     --     --     --     --     61    IX.40 --     --     --     30     --     --     50    IX.42 --     --     --     9      --     --     72    IX.55 --     --     --     --     --     --     83    IX.61 --     --     --     86     --     --     61    IX.73 --     --     --     100    --     --     72    IX.75 --     --     --     --     --     --     99    IX.82 91     100    --     --     --     --     3    IX.84 97     --     --     --     100    --     97    IX.124          --     --     --     --     --     --     65    IX.126          --     --     --     --     --     --     94    IX.127          --     --     --     --     --     --     50    X.3   100    --     100    52     --     --     94    X.26  --     --     --     82     --     --     88    X.32  54     --     --     --     --     --     96    XI.5  100    --     100    30     --     13     100    XI.9  --     --     --     --     26     --     99    XI.11 84     100    --     --     100    --     95    XI.23 40     14     --     --     48     --     98    XI.24 --     --     --     --     95     --     86    XI.25 41     100    --     --     --     --     97    XI.30 --     81     --     --     --     --     4    XI.31 --     29     --     --     --     --     14    XI.34 100    100    --     --     99     --     100    XI.35 97     100    --     --     98     --     98    XI.36 100    100    --     --     100    --     92    XI.38 100    100    --     --     52     --     93    XI.40 36     --     100    100    95     77     100    XI.87 82     100    --     --     92     --     100    XI.102          --     --     2      --     --     --     0    XI.108          --     100    --     --     93     --     92    XI.109          100    --     --     --     35     --     93    XI.110          70     --     96     --     59     --     90    XI.125          100    100    --     --     80     --     97    XI.127          100    --     100    26     --     --     0    XII.1 86     --     9      --     100    --     95    XII.3 100    --     46     9      65     --     88    XII.4 100    --     93     49     --     67     98    XII.5 37     --     0      72     --     --     89    XII.8 59     --     4      --     100    --     96    XII.9 --     42     --     --     --     --     68    XII.11          81     100    --     --     50     --     100    XII.12          73     100    --     --     --     --     97    XII.13          43     20     --     --     --     --     76    XII.14          93     100    --     --     95     --     93    XII.15          47     11     --     --     --     --     94    XII.19          50     30     --     --     --     --     69    XII.23          95     100    --     --     97     --     97    XII.25          100    100    --     --     56     --     99    XII.26          73     100    --     --     77     --     99    XII.27          --     98     --     --     --     --     --    XII.28          100    100    --     --     --     --     84    XII.29          --     100    --     --     100    --     99    XII.30          15     100    --     --     --     --     94    XII.31          73     --     22     --     100    --     95    XII.32          100    100    --     --     98     --     99    XII.33          45     37     --     --     --     --     --    XII.35          100    87     --     --     95     --     98    XII.49          38     --     18     --     97     --     95    XII.51          40     8      --     --     51     --     91    XII.54          100    80     --     --     100    --     98    XII.55          96     --     --     --     100    --     90    XII.68          53     --     --     --     --     --     0    XII.128          100    100    --     --     26     --     61    XII.129          100    100    --     --     86     --     89    XII.130          --     77     --     --     5      --     87    XII.131          87     --     26     --     54     --     86    XII.132          98     100    --     --     --     --     31    XII.133          99     --     85     --     6      --     0    XII.134          75     --     88     --     97     --     0    XII.142          54     100    --     --     92     --     95    XII.143          48     39     --     --     65     --     94    XII.144          100    100    --     --     --     --     53    XII.145          --     100    --     --     32     --     97    XII.146          --     45     --     --     --     --     69    XII.147          39     56     --     --     --     --     37    XII.148          97     97     --     --     --     --     84    XIII.1          35     --     --     --     --     --     89    XIII.2          95     100    --     --     100    --     98    XIII.3          79     84     --     --     88     --     99    XIII.4          100    100    --     --     100    --     96    XIII.6          79     --     --     --     96     --     100    XIII.7          88     100    --     --     100    --     99    XIII.9          91     --     100    --     18     --     93    XIII.10          94     --     100    --     32     --     96    XIII.11          94     --     83     --     96     --     92    XIII.14          --     --     --     --     7      --     95    XIII.15          43     77     --     --     --     --     94    XIII.16          89     --     --     --     89     --     96    XIII.17          74     100    --     --     100    --     97    XIII.18          85     100    --     --     96     --     99    XIII.20          94     --     90     --     48     --     0    XIII.24          89     100    --     --     45     --     100    XIII.27          69     --     --     --     77     --     99    XIII.28          100    100    --     --     100    --     96    XIII.29          95     100    --     --     100    --     97    XIII.40          100    --     5      100    100    --     100    XIII.41          100    --     95     --     100    --     96    XIII.42          98     --     35     --     100    --     95    XIII.45          81     --     44     --     91     --     97    XIII.63          --     --     --     98     --     --     100    XIII.64          85     --     97     --     98     --     97    XIII.65          73     --     42     --     100    --     98    XIII.66          100    93     --     --     --     --     31    XIII.69          84     18     --     --     --     --     63    XIII.70          --     --     22     --     --     --     0    XIII.101          79     98     --     --     99     --     100    XIII.110          100    --     64     27     --     79     94    XIII.114          96     100    --     --     18     --     97    XIII.115          97     100    --     --     45     --     91    XIII.116          --     100    --     --     19     --     100    XIII.117          100    --     100    77     --     --     100    XIII.119          --     --     13     29     82     53     91    XIII.122          95     100    --     --     35     --     100    XIII.124          78     --     12     --     --     --     0    XIII.133          100    --     100    100    --     50     100    XIII.134          97     --     100    100    --     --     100    XIII.143          --     --     --     --     --     --     41    XIV.1 45     --     15     100    --     33     0    XV.1  82     --     18     80     --     70     9    XVI.1 --     34     --     --     --     --     50    XVI.2 --     --     --     --     7      --     82    XVI.3 59     --     --     --     97     --     94    XVI.5 56     --     39     --     62     --     100    XVI.6 88     97     --     --     96     --     100    XVI.7 --     --     --     --     --     --     0    XVI.8 42     100    --     --     --     --     89    XVI.9 68     29     --     --     --     --     12    XVI.10          100    --     65     100    --     53     100    XVI.11          --     --     2      --     --     --     0    XVI.12          20     18     --     --     --     --     81    XVI.13          --     --     --     --     --     --     32    XVI.14          --     --     --     --     --     --     0    XVI.15          --     --     53     --     48     --     94    XVI.16          100    100    --     --     --     --     94    XVI.17          46     45     --     --     --     --     24    XVI.18          25     48     --     --     --     --     43    XVI.19          26     --     --     --     --     --     0    XVI.20          --     --     --     --     --     --     42    XVI.21          82     --     100    --     8      --     100    XVI.22          44     --     --     --     --     --     41    XVI.23          --     --     --     --     --     --     38    XVI.24          81     100    --     --     85     --     97    XVII.1          30     --     7      74     --     50     0    XVII.2          24     --     1      --     --     27     0    XVII.3          --     --     0      --     --     87     0    XVII.4          11     --     0      --     --     --     0    XVII.5          32     --     7      --     --     --     0    XVII.6          --     --     --     --     --     --     0    XVII.7          49     --     7      --     --     30     0    XVIII.1          95     --     100    35     --     80     92    XVIII.3          --     --     45     100    --     23     98    XVIII.4          96     --     100    15     --     93     94    XVIII.7          --     --     --     --     --     83     0    XVIII.10          49     --     65     --     29     --     100    XVIII.13          100    --     74     --     53     --     0    XVIII.14          56     --     7      --     --     --     0    XVIII.15          62     --     38     --     89     --     100    XVIII.16          55     --     5      --     94     --     100    XIX.1 100    --     15     30     --     100    82    XX.4  91     --     71     8      --     97     0    XX.15 100    --     --     --     94     --     100    XX.27 69     96     --     --     91     --     100    XX.28 31     85     --     --     --     --     73    XX.30 69     100    --     --     91     --     99    XX.52 63     --     100    --     93     --     96    XX.53 97     100    --     --     92     --     100    XX.54 43     3      --     --     --     --     61    XX.65 52     34     --     --     --     --     47    XX.98 85     --     --     --     95     --     100    XX.109          50     100    --     --     100    --     99    XX.110          77     100    --     --     95     --     99    XX.116          68     --     71     --     98     --     96    XX.117          100    98     --     --     96     --     100    XX.118          34     7      --     --     --     --     21    XX.137          47     --     100    --     94     --     95    XX.205          79     100    --     --     --     --     94    XX.218          81     100    --     --     --     --     97    XX.221          42     --     79     --     92     --     99    XX.226          94     --     --     --     100    --     97    XX.227          86     --     51     100    --     --     100    XX.231          88     --     100    --     52     --     100    XX.247          90     100    --     --     100    --     94    XX.251          18     --     79     26     --     --     0    XXI.1 28     --     0      --     --     --     0    __________________________________________________________________________

EXAMPLE 3

The spectrum of nematicidal activity of compounds according to theinvention was investigated in contact assays in the presence of soil anda host plant. Greatest activity was seen against Meloidogyne incognita,Globodera rostochiensis, Pratylenchus brachyurus, Tylenchorhynchusclaytoni, Hoplolaimus columbus and Radopholus similis. Adequate activitywas seen against Rotylenchulus reniformis, and Belonolaimuslongicaudatus.

The following examples demonstrate formulations suitable for applyingthe compounds of the present invention. The amount of ingredient isexpressed in parts by weight or grams per liter as indicated. A *indicates a trademark,

EXAMPLE 4

This example demonstrates granules suitable for soil application. Thegranules can be made by standard techniques such as impregnation,coating, extrusion or agglomeration.

    ______________________________________                             % w/w    ______________________________________    Impregnated granule:                   Active ingredient                                   5                   Wood Rosin      2.5                   Gypsum granules 92.5                   (20-40 mesh)    Coated granule:                   Active ingredient                                   0.5                   `Solvesso`* 200 0.4                   Calcium carbonate granules                                   99.1                   (30-60 mesh)    Slow release granule:                   Active ingredient                                   10                   Polyvinylacetate/vinyl                                   5                   chloride copolymer latex                   Attapulgus granules                                   85    ______________________________________

EXAMPLE 5

This Example demonstrates formulations for use as a spray. The compoundscan be formulated as wettable powders, water dispersible granules,suspension concentrates, emulsifiable concentrates, emulsions ormicrocapsule suspensions for application diluted in water.

    ______________________________________                                   g/l    ______________________________________    Emulsifiable concentrate:                  Active ingredient                                   250                  Calcium dodecyl- 50                  benzene sulfonate                  Nonyl phenol ethoxylate                                   50                  Alkylbenzene solvent                                   to 1 liter    ______________________________________                                   % w/w    ______________________________________    Wettable powder:                  Liquid active ingredient                                   40                  lignosulfonate dispersant                                    5                  silica           25                  sodium lauryl sulfate                                    3                  china clay (kaolin)                                   27    Microcapsule suspension:                  Liquid active ingredient                                   250                  toluene diisocyanate                                   10                  polymethylene polyphenyl                                   20                  isocyanate                  nonyl phenol ethoxylate                                    6                  lignosulfonate dispersant                                   15                  xanthan gum       1                  bentonite        10                  biocide `Proxel`*                                     0.1                  sodium carbonate  5                  water            to 1 liter    ______________________________________

The microcapsule suspensions can be used as a spray, soil drench or asan intermediate to prepare slow release granules for application to thesoil.

    ______________________________________                                   g/l    ______________________________________    Suspension concentrate:                    Solid active ingredient                                   400                    lignosulfonate dispersant                                   50                    sodium lauryl sulfate                                   30                    xanthan gum     1                    biocide `Proxel`*                                     0.1                    bentonite      10                    water          to 1 liter    ______________________________________

EXAMPLE 6

This Example demonstrates formulations suitable for use as seedtreatments in conventional application machinery.

    ______________________________________                                  % w/w    ______________________________________    Dry seed treatment:                   Active ingredient                                  20                   dodecyl benzene                                  3                   Rubine Toner (dyestuff)                                  2.7                   Talc           53.3                   Silica         to 100%    ______________________________________

The suspension concentrate and microcapsule suspension of Example 5 canbe used as flowable concentrates for seed treatment.

EXAMPLE 7

This Example demonstrates the formulation of the compounds forelectrostatic spraying.

    ______________________________________                   g/l    ______________________________________    Active ingredient                     200    N-methylpyrrolidone                      50    Soyabean oil     120    `Solvesso`* 200  to 1 liter    ______________________________________

EXAMPLE 8

This Example demonstrates a formulation suitable for use as a bait.

    ______________________________________                     % w/w    ______________________________________    Active ingredient  0.25    Icing sugar        99.65    Butylated hydroxy toluene                       0.10    ______________________________________

EXAMPLE 9

This Example demonstrates a formulation suitable for use as a bolus.

    ______________________________________                     mg    ______________________________________    Active ingredient  1300    Sodium starch glycollate                       300    Microcrystalline cellulose                       1200    Lactose            2920    Povidone           250    Magnesium stearate 30    ______________________________________

EXAMPLE 10

This Example demonstrates a formulation suitable for use as aninjectable suspension.

    ______________________________________                       mg    ______________________________________    Active ingredient    40    Sodium metabisulfite  1    Polysorbate 80        1    Sodium methyl hydroxybenzoate                          2    Water to              1 ml    ______________________________________

EXAMPLE 11

This Example demonstrates a formulation suitable for use as aninjectable solution.

    ______________________________________                          mg    ______________________________________           Active ingredient                            40           Sodium citrate    6           Citric acid       1           Sodium chloride   7           Chlorcresol       1           Water to          1 ml    ______________________________________

EXAMPLE 12

This Example demonstrates a formulation suitable for use as an oralsuspension.

    ______________________________________                    g    ______________________________________    Active ingredient     100.0    Polysorbate 80        2.0    Xanthan gum           5.0    Colloidal silicon dioxide                          10.0    Methyl hydroxybenzoate                          1.5    Citric acid monohydrate                          10.0    Sodium citrate        10.0    Purified water to     1000.0   ml    ______________________________________     ##STR21##

We claim:
 1. A compound of formula (I),

    R--S(O).sub.n CH.sub.2 CH═CF.sub.2

or a salt thereof, wherein n is 0, 1 or 2; and R is a group of formula(XIX) to (XXI), ##STR22## wherein: the --S(O)nCH2CH2CH═CF2 group is atleast one of R2, R3, R4, R5 or R6; the remainder of R2, R3, R4, R5 andR6 are each independently hydrogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,cycloalkyl, alkylcycloalkyl, alkoxy, alkenyloxy, alkynyloxy,hydroxyalkyl, alkoxyalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted aryloxy, optionallysubstituted arylalkoxy, optionally substituted aryloxyalkyl, optionallysubstituted heteroaryloxy, optionally substituted heteroarylalkoxy,optionally substituted heteroaryloxyalkyl, haloalkyl, haloalkenyl,haloalkynyl, haloalkoxy, haloalkenyloxy, haloalkynyloxy, halogen,hydroxy, cyano, nitro, --NR7R8, --NR7COR8, --NR7CSR8, --NR7SO2R8,--N(SO2R7)(SO2R8), --COR7, --CONR7R8, -alkylCONR7R8, --CR7N8, --COOR7,--OCOR7, --SR7, --SOR7, --SO2R7, -alkylSR7, -alkylSOR7, -alkylSO2R7,--OSO2R7, --SO2NR7R8, --CSNR7R8, --SiR7R8R9, --OCH2O2R7, --OCH2CH2CO2R7,--CONR7SO2R8, -alkylCONR7SO2R8, --NHCONR7R8, --NHCSNR7R8, or an adjacentpair R2, R3, R4, R5 and R6 when taken together form a fused 5- or6-membered carbocyclic or heterocyclic ring; and R7, R8 and R9 are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted alkenyl, alkynyl, optionally substituted aryl or optionallysubstituted arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, halogen, orhydroxy.
 2. A compound according to claim 1, wherein:the--S(O)nCH2CH2CH═CF2 group is at least one of R2, R3, R4, R5 or R6; theremainder of R2, R3, R4, R5 and R6 are each independently hydrogen,optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl,optionally substituted C2-6 alkynyl, C3-6 cycloalkyl, C4-7alkylcycloalkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6hydroxyalkyl, C2-6 monoalkoxyalkyl, C3-6 dialkoxyalkyl, optionallysubstituted C6-10 aryl, optionally substituted C6-10 aryl C1-2 alkylgroup, optionally substituted 5- or 6-membered heteroaryl, optionallysubstituted 5- or 6-membered heteroaryl-C1-6 alkyl, optionallysubstituted C6-10 aryloxy, optionally substituted C6-10 aryl-C1-2alkoxy, C6-10 aryloxy-C1-6 alkyl, optionally substituted 5- or6-membered heteroaryloxy, optionally substituted 5- or 6-memberedheteroaryl-C1-6 alkoxy, 5- or 6-membered heteroaryloxy-C1-2 alkyl, C1-6haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 haloalkoxy, C2-6haloalkenyloxy, C2-6 haloalknyloxy, halogen, hydroxy, cyano, nitro,--NR7R8, --NR7COR8, --NR7CSR8, --NR7SO2R8, --N(SO2-R7)(SO2-R8), --COR7,--CONR7R8, --C1-6 alkylCONR7R8, --CR7NR8, --COOR7, --OCOR7, --SR7, SOR7,--SO2R7, --C1-6 alkylSR7, --C1-6 alkylSOR7, --C1-6 alkyl-SO2R7,--OSO2R7, --SO2NR7R8, --CSNR7R8, --SiR7R8R9, --OCH2CO2R7,--OCH2CH2CO2R7, --CONR7SO2R8, --C1-6 alkylCONR7SO2R8, --NHCONR7R8, or--NHCSNR7R8; or an adjacent pair of R2, R3, R4, R5 and R6 when takentogether form a fused 5- or 6-membered carbocyclic or heterocyclic ring;and R7, R8 and R9 are each independently hydrogen, optionallysubstituted C1-6 alkyl, optionally substituted C2-6 alkenyl, C2-6alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, optionallysubstituted C6-10 aryl or optionally substituted C6-10 aryl-C1-6 alkyl,halogen or hydroxy.
 3. A compound according to claim 2, wherein when anyone of R2 to R9 is:substituted alkyl it comprises one or moresubstituents chosen from halogen, nitro, cyano, COOR7 or a salt thereof,hydroxy, alkoxy, alkoxyimino, alkoxycarbonyl, carbomyl, mono- ordi-alkylcarbamoyl, amino, mono- or di- alkylamino, acylamido,alkanesulfonyl and arylsulfonyl; substituted alkenyl it comprises one ormore substituents chosen from halogen, COOR7 or a salt thereof, hydroxy,nitro and cyano; substituted aryl, arylalkyl, aryloxy, arylalkoxy,heteroaryl, heteroarylalkyl, heteroaryloxy or heteroarylalkoxy itcomprises one or more substituents chosen from alkyl, alkoxy, haloalkyl,halogen, hydroxy, COOR7 or a salt thereof, aminosulfonyl, cyano andnitro.
 4. A compound according to either of claims 2 or 3 wherein whenany one of R2 to R6 is --SR7, it is optionally substituted C1-6alkylthio, C2-6 alkenylthio, C2-6 alkenylthio, C1-6 haloalkylthio, C2-6haloalkenylthio, C2-6 haloalkynylthio or C6-10 arylthio.
 5. A compoundaccording to claim 1 wherein:the --S(O)nCH2CH2CH═CF2 group is at leastone of R2, R3, R4, R5 or R6; the remainder of R2, R3, R4, R5 and R6 areeach independently hydrogen; nitro; halogen; cyano; --CH═NOH; C1-4alkyl; C1-4 haloalkyl; C2-4 alkenyl; C2-4 haloalkenyl; cyclopropyl;hydroxy; C1-4 alkoxy; C2-4 alkoxyalkyl; --COOH; C2-4 alkoxycarbonyl;C3-4 haloalkenyloxycarbonyl; --CONH2; mono or di-C1-2alkylaminocarbonyl; C2-4 alkanecarbonyl; phenyl optionally mono- or di-substituted with groups independently chosen from halogen, nitro, C1-4alkyl, C1-4 alkoxy or aminosulfonyl; --CONHSO2-C1-4 alkyl; benzyloptionally mono- or di- substituted with groups independently chosenfrom halogen, nitro, C1-4 alkyl or C1-4 alkoxy; phenoxy optionally mono-or di- substituted with groups independently chosen from halogen, cyano,C1-4 alkyl or C1-4 alkoxy; amino optionally mono- or di- substitutedwith C1-4 alkyl groups; --SH; C1-4 alkylthio; benzylthio optionallymono- or di- substituted with groups independently chosen from halogenor C1-4 haloalkyl; C2-4 alkenylthio; C2-4 haloalkenylthio; a secondS(O)nCH2CH2CH═CF2 group; C1-4 alkanesulfonyl; C1-4 haloalkanesulfonyl;fluorosulfonyl; mono- or di- C1-4 alkylsulfamoyl; a 5- or 6-memberedheteroaryl group optionally substituted with halogen; or any adjacentpair forms a fused 5- or 6-membered carbocyclic or heterocyclic ring. 6.A process for the preparation of a compound of any one of claims 1 to 3,when n is 1 or 2, which comprises oxidation of the correspondinglysubstituted compound of formula (I) when n is
 0. 7. An agriculturalcomposition comprising a compound of any one of claims 1 to 3 as theactive ingredient in admixture with an agriculturally acceptable diluentor carrier.
 8. An agricultural composition according to claim 7, furthercomprising a surface active material.
 9. An agricultural compositionaccording to claim 7, further comprising at least one other activeingredient which is an insecticide, fungicide, bactericide, acaricide orother biologically active compound.
 10. A process for preparing anagricultural composition comprising a compound of any one of claims 1 to3, comprising mixing a compound of any one of claims 1 to 3 with anagriculturally acceptable diluent or carrier.
 11. A method for killingor controlling nematode, insect or acarid pests comprising applying acompound of any one of claims 1 to 2 to the pests, their habitat, or aplant susceptible to attack by the pests.